ABOUT ALZHEIMER'S DISEASE

Alzheimer's disease
Classification and external resources
Comparison of a normal aged brain (left) and an Alzheimer's patient's brain (right). Differential characteristics are pointed out.
ICD-10	G 30., F 00.
ICD-9	331.0, 290.1
OMIM	104300
DiseasesDB	490
MedlinePlus	000760
eMedicine	neuro/13
MeSH	D000544
GeneReviews	[1]

Alzheimer's disease (AD), also called Alzheimer disease, senile dementia of the Alzheimer type (SDAT), primary degenerative dementia of the Alzheimer's type (PDDAT), or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Most often, it is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.

Although the course of Alzheimer's disease is unique for every individual, there are many common symptoms. The earliest observable symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the early stages, the most commonly recognised symptom is inability to acquire new memories, such as difficulty in recalling recently observed facts. When AD is suspected, the diagnosis is usually confirmed with behavioural assessments and cognitive tests, often followed by a brain scan if available.

As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline. Gradually, bodily functions are lost, ultimately leading to death. Individual prognosis is difficult to assess, as the duration of the disease varies. AD develops for an indeterminate period of time before becoming fully apparent, and it can progress undiagnosed for years. The mean life expectancy following diagnosis is approximately seven years. Fewer than three percent of individuals live more than fourteen years after diagnosis.

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. Currently used treatments offer a small symptomatic benefit; no treatments to delay or halt the progression of the disease are, as of yet, available. As of 2008^[update], more than 500 clinical trials have been conducted for identification of a possible treatment for AD, but it is unknown if any of the tested intervention strategies will show promising results. A number of non-invasive, life-style habits have been suggested for the prevention of Alzheimer's disease, but there is a lack of adequate evidence for a link between these recommendations and reduced degeneration. Mental stimulation, exercise, and a balanced diet are suggested, as both a possible prevention and a sensible way of managing the disease.

Because AD cannot be cured and is degenerative, management of patients is essential. The role of the main caregiver is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a great burden on caregivers; the pressures can be wide-ranging, involving social, psychological, physical, and economic elements of the caregiver's life. In developed countries, AD is one of the most costly diseases to society.

Characteristics

The disease course is divided into four stages, with progressive patterns of cognitive and functional impairments.

Pre-dementia

The first symptoms are often mistaken as related to aging or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of AD. These early symptoms can affect the most complex daily living activities. The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.

Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships), can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. The preclinical stage of the disease has also been termed mild cognitive impairment, but whether this term corresponds to a different diagnostic stage or identifies the first step of AD is a matter of dispute.

Early

In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small portion of them, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. AD does not affect all memory capacities equally. Older memories of the person'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 lesser degree than new facts or memories.

Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which lead to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of adequately communicating basic ideas. While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present but they are commonly unnoticed. As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities.

Moderate

Progressive deterioration eventually hinders independence; with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory, which was previously intact, becomes impaired.

Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Sundowning can also appear. Approximately 30% of patients develop illusionary misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to other long-term care facilities.

Advanced

During this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, patients can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results. Patients will ultimately not be able to perform even the most simple tasks without assistance. Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves. AD is a terminal illness with the cause of death typically being an external factor such as infection of pressure ulcers or pneumonia, not the disease itself.

Causes

Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau protein

Several competing hypotheses exist trying to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.

In 1991, the amyloid hypothesis postulated that amyloid beta (A?) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid beta precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age. Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, A? deposition precedes clinical AD. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.

An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque A? oligomers (aggregates of many monomers) as the primary pathogenic form of A?. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication. One receptor for A? oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt-Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.

In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21). DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the aging brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.

A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss. This observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells. Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.

Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Demyelination leads to axonal transport disruptions, leading to loss of neurons that become stale. Iron released during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as amyloid-beta and tau.

Oxidative stress is a significant cause in the formation of the pathology.

AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine (in addition to its neurotransmitter role) that locally diffuses from "varicosities" as an endogenous antiinflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus. It has been shown that norepinephrine stimulates mouse microglia to suppress A?-induced production of cytokines and their phagocytosis of A?. This suggests that degeneration of the locus ceruleus might be responsible for increased A? deposition in AD brains.

Pathophysiology

Main article: Biochemistry of Alzheimer's disease

Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer's disease of presenile onset. Silver impregnation.

Neuropathology

Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss 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. Studies using MRI and PET have documented reductions in the size of specific brain regions in patients as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar Images from healthy older adults.

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid-beta peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of AD patients have a greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in AD patient's brains.

Biochemistry

Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.

Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid (also written as A-beta or A?). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques.

In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.

Disease mechanism

Exactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology of AD is not known. The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as the central event triggering neuron 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 programmed cell death (apoptosis). It is also known that A? selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.

Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response.

Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain derived neurotrophic factor (BDNF) have been described in AD.

Genetics

The vast majority of cases of Alzheimer's disease are sporadic, meaning that they are not genetically inherited although some genes may act as risk factors. On the other hand, around 0.1% of the cases are familial forms of autosomal-dominant inheritance, which usually have an onset before age 65.

Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: amyloid precursor protein (APP) and presenilins 1 and 2. Most mutations in the APP and presenilin genes increase the production of a small protein called A?42, which is the main component of senile plaques. Some of the mutations merely alter the size ratio between A?42 and the other major forms—e.g., A?40—without increasing A?42 levels. This suggests that presenilin mutations can cause disease even if they lower the total amount of A? produced and may point to other roles of presenilin or a role for alterations in the function of APP and/or its fragments other than A?.

Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD. Nevertheless genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ?4 allele of the apolipoprotein E (APOE). Between 40 and 80% of patients with AD possess at least one apoE4 allele. The APOE4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. Geneticists agree that numerous other genes also act as risk factors or have protective effects that influence the development of late onset Alzheimer's disease. Over 400 genes have been tested for association with late-onset sporadic AD, most with null results.

Diagnosis

PET scan of the brain of a person with AD showing a loss of function in the temporal lobe

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. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease.

Assessment of intellectual functioning including memory testing can further characterise the state of the disease. Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practicing physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.

Criteria

The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984, extensively updated in 2007. 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. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation. Eight cognitive domains are most commonly impaired in AD—memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association.

Techniques

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, and subtract serial numbers.

Neuropsychological tests such as the mini-mental state examination (MMSE), are widely used to evaluate the cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. Neurological examination in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from other diseases processes, including other causes of dementia.

Further neurological examinations are crucial in the differential diagnosis of AD and other diseases. Interviews with family members are also utilised 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 person's mental function. A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits. Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.

Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins, both total tau protein and phosphorylated tau_181P protein concentrations. Searching for these proteins using a spinal tap can predict the onset of Alzheimer's with a sensitivity of between 94% and 100%. When used in conjunction with existing neuroimaging techniques, doctors can identify patients with significant memory loss who are already developing the disease. Spinal fluid tests are commercially available, unlike the latest neuroimaging technology. Alzheimer's was diagnosed in one-third of the people who did not have any symptoms in a 2010 study, meaning that disease progression occurs well before symptoms occur.

Supplemental testing provides extra information on some features of the disease or is used to rule out other diagnoses. Blood tests can identify other causes for dementia than AD—causes which may, in rare cases, be reversible. It is common to perform thyroid function tests, assess B12, rule out syphillis, rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals (e.g. lead, mercury) and anemia. (See differential diagnosis for Dementia). (It is also necessary to rule out delirium).

Psychological tests for depression are employed, since depression can either be concurrent with AD (see Depression of Alzheimer disease), an early sign of cognitive impairment, or even the cause.

Imaging

When available as a diagnostic tool, single photon emission computed tomography (SPECT) and positron emission tomography (PET) neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving mental status examination. In a person already having dementia, SPECT appears to be superior in differentiating Alzheimer's disease from other possible causes, compared with the usual attempts employing mental testing and medical history analysis. Advances have led to the proposal of new diagnostic criteria.

A new technique known as PiB PET has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a tracer that binds selectively to the A-beta deposits. The PiB-PET compound uses carbon-11 PET scanning. Recent studies suggest that PiB-PET is 86% accurate in predicting which people with mild cognitive impairment will develop Alzheimer's disease within two years, and 92% accurate in ruling out the likelihood of developing Alzheimer's.

A similar PET scanning radiopharmaceutical compound called (E)-4-(2-(6-(2-(2-(2-([¹⁸F]-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine, or ¹⁸F AV-45, or florbetapir-fluorine-18, or simply florbetapir, contains the longer-lasting radionuclide fluorine-18, has recently been created, and tested as a possible diagnostic tool in Alzheimer's patients. Florbetapir, like PiB, binds to beta-amyloid, but due to its use of fluorine-18 has a half-life of 110 minutes, in contrast to PiB's radioactive half life of 20 minutes. Wong et al. found that the longer life allowed the tracer to accumulate significantly more in the brains of the AD patients, particularly in the regions known to be associated with beta-amyloid deposits.

One review predicted that amyloid imaging is likely to be used in conjunction with other markers rather than as an alternative.

Volumetric MRI can detect changes in the size of brain regions. Measuring those regions that atrophy during the progress of Alzheimer's disease is showing promise as a diagnostic indicator. It may prove less expensive than other imaging methods currently under study.

Non-Imaging biomarkers

Recent studies suggest that brain metabolite levels may be utilized as biomarkers for Alzheimer's disease.

Three antibodies have been found that could act as biomarkers for AD.

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.

At present, there is no definitive evidence to support that any particular measure is effective in preventing AD. Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. However, 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 these factors can help to prevent AD.

Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD, statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease. 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. Its beneficial cardiovascular effect has been proposed as the mechanism of action. There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD.

Reviews on the use of vitamins have not found enough evidence of efficacy to recommend vitamin C, E, or folic acid with or without vitamin B₁₂, as preventive or treatment agents in AD. Additionally vitamin E is associated with important health risks. Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline. Docosahexaenoic acid, an Omega 3 fatty acid, has not been found to slow decline.

Long-term usage of non-steroidal anti-inflammatory drug (NSAIDs) is associated with a reduced likelihood of developing AD. Human postmortem studies, in animal models, or in vitro investigations also support the notion that NSAIDs can reduce inflammation related to amyloid plaques. However trials investigating their use as palliative treatment have failed to show positive results while no prevention trial has been completed. Curcumin from the curry spice turmeric has shown some effectiveness in preventing brain damage in mouse models due to its anti-inflammatory properties. Hormone replacement therapy, although previously used, is no longer thought to prevent dementia and in some cases may even be related to it. There is inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia, and a recent study concludes that it has no effect in reducing the rate of AD incidence. A 21-year study found that coffee drinkers of 3–5 cups per day at midlife had a 65% reduction in risk of dementia in late-life.

People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's disease. This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations. Education delays the onset of AD syndrome, but is not related to earlier death after diagnosis. Physical activity is also associated with a reduced risk of AD.

Medical marijuana appears to be effective in delaying Alzheimer's Disease. The active ingredient in marijuana, THC, prevents the formation of deposits in the brain associated with Alzheimer's disease. THC was found to inhibit acetylcholinesterase more effectively than commercially marketed drugs. THC was also found to delay amylogenesis.

Some studies have shown an increased risk of developing AD with environmental factors such the intake of metals, particularly aluminium, or exposure to solvents. The quality of some of these studies has been criticised, and other studies have concluded that there is no relationship between these environmental factors and the development of AD.

While some studies suggest that extremely low frequency electromagnetic fields may increase the risk for Alzheimer's disease, reviewers found that further epidemiological and laboratory investigations of this hypothesis are needed. Smoking is a significant AD risk factor. Systemic markers of the innate immune system are risk factors for late-onset AD.

Management

There is no 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

Three-dimensional molecular model of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms

Molecular structure of memantine, a medication approved for advanced AD symptoms

Four medications are currently approved by regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to treat the cognitive manifestations of AD: 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.

Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease. Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. As of 2008^[update], the cholinesterase inhibitors approved for the management of AD symptoms are donepezil (brand name Aricept), galantamine (Razadyne), and rivastigmine (branded as Exelon and Exelon Patch). There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease, and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia. The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD. The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% 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 production.

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. Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda), is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer's disease. Its effects in the initial stages of AD are unknown. Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue. The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".

Antipsychotic drugs are modestly useful in reducing aggression and psychosis in Alzheimer's patients with behavioural problems, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use. When used in the long-term, they have been shown to associate with increased mortality.

Patients with Alzheimer’s disease who have taken Huperzine A have improved general cognitive function, global clinical status, functional performance and reduced behavioural disturbance compared to patients taking placebos, according to a Cochrane Review.

Psychosocial intervention

A specifically designed room for sensory integration therapy, also called 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 behaviour-, emotion-, cognition- or stimulation-oriented approaches. Research on efficacy is unavailable and rarely specific to AD, focusing instead on dementia in general.

Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning, but can help to reduce some specific problem behaviours, such as incontinence. There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering.

Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called 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. 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. Simulated presence therapy (SPT) is based on attachment theories and involves playing a recording with voices of the closest relatives of the person with Alzheimer's disease. There is partial evidence indicating that SPT may reduce challenging behaviours. 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.

The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction 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 or her 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, although in some studies these effects were transient and negative effects, such as frustration, have also been reported.

Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities. Stimulation has modest support for improving behaviour, 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 change in the person's routine.

Caregiving

Further information: Caregiving and dementia

Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving essentially is the treatment and must be carefully managed over the course of the disease.

During the early and moderate stages, modifications to the living environment and lifestyle can increase patient safety and reduce caretaker burden. Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labelling of household items to cue the person with the disease or the use of modified daily life objects. The patient may also become incapable of feeding themselves, so they require food in smaller pieces or pureed. When swallowing difficulties arise, the use of feeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members. The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with AD or their caregivers.

As the disease progresses, different medical issues can appear, such as oral and dental disease, pressure ulcers, malnutrition, hygiene problems, or respiratory, skin, or eye infections. Careful management can prevent them, while professional treatment is needed when they do arise. During the final stages of the disease, treatment is centred on relieving discomfort until death.

A small recent study in the US concluded that patients whose caregivers had a realistic understanding of the prognosis and clinical complications of late dementia were less likely to receive aggressive treatment near the end of life.

Prognosis

Disability-adjusted life year for Alzheimer and other dementias per 100,000 inhabitants in 2004.

no data

? 50

50–70

70–90

90–110

110–130

130–150

150–170

170–190

190–210

210–230

230–250

? 250

The early stages of Alzheimer's disease are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living.

Life expectancy of the population with the disease is reduced. The mean life expectancy following diagnosis is approximately seven years. Fewer than 3% of patients live more than fourteen years. Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases such as heart problems, diabetes or history of alcohol abuse are also related with shortened survival. While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger. Men have a less favourable survival prognosis than women.

The disease is the underlying cause of death in 70% of all cases. Pneumonia and dehydration are the most frequent immediate causes of death, while cancer is a less frequent cause of death than in the general population.

Epidemiology

Incidence rates
after age 65
Age	New affected per thousand person–years
65–69	3
70–74	6
75–79	9
80–84	23
85–89	40
90–	69

Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence is the total number of cases of the disease in the population at any given time.

Regarding incidence, cohort longitudinal studies (studies where a disease-free population is followed over the years) provide rates between 10 and 15 per thousand person–years for all dementias and 5–8 for AD, which means that half of new dementia cases each year are AD. Advancing age is a primary risk factor for the disease and incidence rates are not equal for all ages: every five years after the age of 65, the risk of acquiring the disease approximately doubles, increasing from 3 to as much as 69 per thousand person years. There are also sex differences in the incidence rates, women having a higher risk of developing AD particularly in the population older than 85.

Prevalence of AD in populations is dependent upon different factors including incidence and survival. Since the incidence of AD increases with age, it is particularly important to include the mean age of the population of interest. In the United States, Alzheimer prevalence was estimated to be 1.6% in 2000 both overall and in the 65–74 age group, with the rate increasing to 19% in the 75–84 group and to 42% in the greater than 84 group. Prevalence rates in less developed regions are lower.^{[dead
link]} The World Health Organization estimated that in 2005, 0.379% of people worldwide had dementia, and that the prevalence would increase to 0.441% in 2015 and to 0.556% in 2030. Other studies have reached similar conclusions. Another study estimated that in 2006, 0.40% of the world population (range 0.17–0.89%; absolute number 26.6 million, range 11.4–59.4 million) were afflicted by AD, and that the prevalence rate would triple and the absolute number would quadruple by 2050.

History

Alois Alzheimer's patient Auguste Deter in 1902. Hers was the first described case of what became known as Alzheimer's disease.

The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia. It was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alzheimer followed her until she died in 1906, when he first reported the case publicly. During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease. The disease was first described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D. He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.

For most of the 20th 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 on AD 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 that they had different causes. This eventually led to the diagnosis of Alzheimer's disease independently of age. 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.

Society and culture

Social costs

Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for society in Europe and the United States, while their cost in other countries such as Argentina, or South Korea, is also high and rising. These costs will probably increase with the ageing of society, becoming an important social problem. AD-associated costs include direct medical costs such as nursing home care, direct nonmedical costs such as in-home day care, and indirect costs such as lost productivity of both patient and caregiver. Numbers vary between studies but dementia costs worldwide have been calculated around $160 billion, while costs of Alzheimer in the United States may be $100 billion each year.

The greatest origin of costs for society is the long-term care by health care professionals and particularly institutionalisation, which corresponds to 2/3 of the total costs for society. The cost of living at home is also very high, especially when informal costs for the family, such as caregiving time and caregiver's lost earnings, are taken into account.

Costs increase with dementia severity and the presence of behavioural disturbances, and are related to the increased caregiving time required for the provision of physical care. Therefore any treatment that slows cognitive decline, delays institutionalisation or reduces caregivers' hours will have economic benefits. Economic evaluations of current treatments have shown positive results.

Caregiving burden

Further information: Caregiving and dementia

The role of the main caregiver is often taken by the spouse or a close relative.^{[dead
link]} Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical or economic aspects. Home care is usually preferred by patients and families. This option also delays or eliminates the need for more professional and costly levels of care. Nevertheless two-thirds of nursing home residents have dementias.

Dementia caregivers are subject to high rates of physical and mental disorders. Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the carer being a spouse, demanding behaviours of the cared person such as depression, behavioural disturbances, hallucinations, sleep problems or walking disruptions and social isolation. Regarding economic problems, family caregivers often give up time from work to spend 47 hours per week on average with the person with AD, while the costs of caring for them are high. Direct and indirect costs of caring for an Alzheimer's patient average between $18,000 and $77,500 per year in the United States, depending on the study.^{[dead
link]}

Cognitive behavioural therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.

Notable cases

Further information: Alzheimer's in the media

Charlton Heston and Ronald Reagan at a meeting in the White House. Both of them would later develop Alzheimer's disease.

As Alzheimer's disease is highly prevalent, many notable people have developed it. Well-known examples are former United States President Ronald Reagan and Irish writer Iris Murdoch, both of whom were the subjects of scientific articles examining how their cognitive capacities deteriorated with the disease. Other cases include the retired footballer Ferenc Puskas, the former Prime Ministers Harold Wilson (United Kingdom) and Adolfo Suárez (Spain), the actress Rita Hayworth, the actor Charlton Heston, the novelist Terry Pratchett, Indian politician George Fernandes, and the 2009 Nobel Prize in Physics recipient Charles K. Kao.

AD has also been portrayed in films such as: Iris (2001), based on John Bayley's memoir of his wife Iris Murdoch; The Notebook (2004), based on Nicholas Sparks' 1996 novel of the same name; A Moment to Remember (2004);Thanmathra (2005); Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name; Away from Her (2006), based on Alice Munro's short story "The Bear Came over the Mountain". Documentaries on Alzheimer's disease include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love's Farewell (2007), both featuring Malcolm Pointon.

Research directions

Main article: Alzheimer's disease clinical research

As of 2010^[update], the safety and efficacy of more than 400 pharmaceutical treatments had been or were being investigated in 858 clinical trials worldwide, and approximately a quarter of these compounds are in Phase III trials; the last step prior to review by regulatory agencies.

One area of clinical research is focused on treating the underlying disease pathology. Reduction of amyloid beta levels is a common target of compounds (such as apomorphine) under investigation. Immunotherapy or vaccination for the amyloid protein is one treatment modality under study. Unlike preventative vaccination, the putative therapy would be used to treat people already diagnosed. It is based upon the concept of training the immune system to recognise, attack, and reverse deposition of amyloid, thereby altering the course of the disease. An example of such a vaccine under investigation was ACC-001, although the trials were suspended in 2008. Another similar agent is bapineuzumab, an antibody designed as identical to the naturally induced anti-amyloid antibody. Other approaches are neuroprotective agents, such as AL-108, and metal-protein interaction attenuation agents, such as PBT2. A TNF? receptor fusion protein, etanercept has showed encouraging results.

In 2008, two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride (trade name rember), a drug that inhibits tau aggregation, and dimebon, an antihistamine. The consecutive Phase-III trial of Dimebon failed to show positive effects in the primary and secondary endpoints.

The possibility that AD could be treated with antiviral medication is suggested by a study showing colocation of herpes simplex virus with amyloid plaques.

Preliminary research on the effects of meditation on retrieving memory and cognitive functions have been encouraging. Limitations of this research can be addressed in future studies with more detailed analyses.

January 2011: The FDA panel voted with definite decision 16-0 to recommend approval of Avid's Amyvid, which is currently used in investigational study. It can detect Alzheimer's brain plaques, but it should requires additional research before it's ready for clinical use.

ABOUT DEMENTIA

Dementia

Dementia (taken from Latin, originally meaning "madness", from de- "without" + ment, the root of mens "mind") is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging. It may be static, the result of a unique global brain injury, or progressive, resulting in long-term decline due to damage or disease in the body. Although dementia is far more common in the geriatric population, it may occur in any stage of adulthood.

This age cutoff is defining, as similar sets of symptoms due to organic brain syndrome or dysfunction, are given different names in populations younger than adult. Up to the end of the 19th century, dementia was a much broader clinical concept. Well into the second half of the 20th century, dementia of the elderly was called senile dementia or senility and viewed as a normal aspect of growing old rather than as being caused by any specific diseases, while Alzheimer's disease was seen as a rare disease of middle age, until the neurologist Robert Katzmann signaled a link between "senile dementia" and Alzheimer's.

Dementia is a non-specific illness syndrome (set of signs and symptoms) in which affected areas of cognition may be memory, attention, language, and problem solving. It is normally required to be present for at least 6 months to be diagnosed; cognitive dysfunction that has been seen only over shorter times, in particular less than weeks, must be termed delirium. In all types of general cognitive dysfunction, higher mental functions are affected first in the process.

Especially in the later stages of the condition, affected persons may be disoriented in time (not knowing what day of the week, day of the month, or even what year it is), in place (not knowing where they are), and in person (not knowing who they are or others around them). Dementia, though often treatable to some degree, is usually due to causes that are progressive and incurable.

Symptoms of dementia can be classified as either reversible or irreversible, depending upon the etiology of the disease. Less than 10% of cases of dementia are due to causes that may presently be reversed with treatment. Causes include many different specific disease processes, in the same way that symptoms of organ dysfunction such as shortness of breath, jaundice, or pain are attributable to many etiologies.

Without careful assessment of history, the short-term syndrome of delirium (often lasting days to weeks) can easily be confused with dementia, because they have all symptoms in common, save duration. Some mental illnesses, including depression and psychosis, may also produce symptoms that must be differentiated from both delirium and dementia.

Chronic use of substances such as alcohol can also predispose the patient to cognitive changes suggestive of dementia, although moderate intake may have a protective effect.

Signs and symptoms

Comorbidities

Dementia is not merely a problem of memory. It reduces the ability to learn, reason, retain or recall past experience and there is also loss of patterns of thoughts, feelings and activities (Gelder et al 2005). Additional mental and behavioral problems often affect people who have dementia, and may influence quality of life, caregivers, and the need for institutionalization. As dementia worsens individuals may neglect themselves and may become disinhibited, the individual may become incontinent as their condition worsens. (Gelder et al 2005).

Depression affects 20–30% of people who have dementia, and about 20% have anxiety. Psychosis (often delusions of persecution) and agitation/aggression also often accompany dementia. Each of these needs to be assessed and treated independent of the underlying dementia.

Risk to self and others

The Canadian Medical Association Journal has reported that driving with dementia could lead to severe injury or even death to self and others. Doctors should advise appropriate testing on when to quit driving.

In the United States, Florida's Baker Act allows law enforcement and the judiciary to force mental evaluation for those suspected of suffering from dementia or other mental incapacities.

In the United Kingdom, as with all mental disorders, where a sufferer could potentially be a danger to themselves or others, they can be detained under the Mental Health Act 1983 for the purposes of assessment, care and treatment. This is a last resort, and usually avoided if the patient has family or friends who can ensure care.

The United Kingdom DVLA (Driving & Vehicle Licensing Agency) states that dementia sufferers who specifically suffer with poor short term memory, disorientation, lack of insight or judgment are almost certainly not fit to drive—and in these instances, the DVLA must be informed so said license can be revoked. They do however acknowledge low-severity cases and early sufferers, and those drivers may be permitted to drive pending medical report.

Causes

Fixed cognitive impairment

Various types of brain injury, occurring as a single event, may cause irreversible but fixed cognitive impairment. Traumatic brain injury may cause generalized damage to the white matter of the brain (diffuse axonal injury), or more localized damage (as also may neurosurgery). A temporary reduction in the brain's supply of blood or oxygen may lead to hypoxic-ischemic injury. Strokes (ischemic stroke, or intracerebral, subarachnoid, subdural or extradural hemorrhage) or infections (meningitis and/or encephalitis) affecting the brain, prolonged epileptic seizures and acute hydrocephalus may also have long-term effects on cognition. Excessive alcohol use may cause alcohol dementia, Wernicke's encephalopathy and/or Korsakoff's psychosis, and certain other recreational drugs may cause substance-induced persisting dementia; once overuse ceases, the cognitive impairment is persistent but not progressive.

Slowly progressive dementia

Dementia which begins gradually and worsens progressively over several years is usually caused by neurodegenerative disease; that is, by conditions affecting only or primarily the neurons of the brain and causing gradual but irreversible loss of function of these cells. Less commonly, a non-degenerative condition may have secondary effects on brain cells, which may or may not be reversible if the condition is treated.

The causes of dementia depend on the age at which symptoms begin. In the elderly population (usually defined in this context as over 65 years of age), a large majority of cases of dementia are caused by Alzheimer's disease, vascular dementia or both. Dementia with Lewy bodies is another fairly common cause, which again may occur alongside either or both of the other causes. Hypothyroidism sometimes causes slowly progressive cognitive impairment as the main symptom, and this may be fully reversible with treatment. Normal pressure hydrocephalus, though relatively rare, is important to recognize since treatment may prevent progression and improve other symptoms of the condition. However, significant cognitive improvement is unusual.

Dementia is much less common under 65 years of age. Alzheimer's disease is still the most frequent cause, but inherited forms of the disease account for a higher proportion of cases in this age group. Frontotemporal lobar degeneration and Huntington's disease account for most of the remaining cases. Vascular dementia also occurs, but this in turn may be due to underlying conditions (including antiphospholipid syndrome, CADASIL, MELAS, homocystinuria, moyamoya and Binswanger's disease). People who receive frequent head trauma, such as boxers or some martial artists, are at risk of dementia pugilistica.

In young adults (up to 40 years of age) who were previously of normal intelligence, it is very rare to develop dementia without other features of neurological disease, or without features of disease elsewhere in the body. Most cases of progressive cognitive disturbance in this age group are caused by psychiatric illness, alcohol or other drugs, or metabolic disturbance. However, certain genetic disorders can cause true neurodegenerative dementia at this age. These include familial Alzheimer's disease, SCA17 (dominant inheritance); adrenoleukodystrophy (X-linked); Gaucher's disease type 3, metachromatic leukodystrophy, Niemann-Pick disease type C, pantothenate kinase-associated neurodegeneration, Tay-Sachs disease and Wilson's disease (all recessive). Wilson's disease is particularly important since cognition can improve with treatment.

At all ages, a substantial proportion of patients who complain of memory difficulty or other cognitive symptoms are suffering from depression rather than a neurodegenerative disease. Vitamin deficiencies and chronic infections may also occur at any age; they usually cause other symptoms before dementia occurs, but occasionally mimic degenerative dementia. These include deficiencies of vitamin B₁₂, folate or niacin, and infective causes including cryptococcal meningitis, HIV, Lyme disease, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, syphilis and Whipple's disease.

Rapidly progressive dementia

Creutzfeldt-Jakob disease typically causes a dementia which worsens over weeks to months, being caused by prions. The common causes of slowly progressive dementia also sometimes present with rapid progression: Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration (including corticobasal degeneration and progressive supranuclear palsy).

On the other hand, encephalopathy or delirium may develop relatively slowly and resemble dementia. Possible causes include brain infection (viral encephalitis, subacute sclerosing panencephalitis, Whipple's disease) or inflammation (limbic encephalitis, Hashimoto's encephalopathy, cerebral vasculitis); tumors such as lymphoma or glioma; drug toxicity (e.g. anticonvulsant drugs); metabolic causes such as liver failure or kidney failure; and chronic subdural hematoma.

Dementia as a feature of other conditions

There are many other medical and neurological conditions in which dementia only occurs late in the illness, or as a minor feature. For example, a proportion of patients with Parkinson's disease develop dementia, though widely varying figures are quoted for this proportion. When dementia occurs in Parkinson's disease, the underlying cause may be dementia with Lewy bodies or Alzheimer's disease, or both. Cognitive impairment also occurs in the Parkinson-plus syndromes of progressive supranuclear palsy and corticobasal degeneration (and the same underlying pathology may cause the clinical syndromes of frontotemporal lobar degeneration). Chronic inflammatory conditions of the brain may affect cognition in the long term, including Behçet's disease, multiple sclerosis, sarcoidosis, Sjögren's syndrome and systemic lupus erythematosus. Although the acute porphyrias may cause episodes of confusion and psychiatric disturbance, dementia is a rare feature of these rare diseases.

Aside from those mentioned above, inherited conditions which may cause dementia alongside other features include:

Alexander disease
Canavan disease
Cerebrotendinous xanthomatosis
DRPLA
Fragile X-associated tremor/ataxia syndrome
Glutaric aciduria type 1
Krabbe's disease
Maple syrup urine disease
Niemann Pick disease type C
Kufs' disease
Neuroacanthocytosis
Organic acidemias
Pelizaeus-Merzbacher disease
Urea cycle disorders
Sanfilippo syndrome type B
Spinocerebellar ataxia type 2
Huntington’s Disease
Multiple sclerosis
Multi-infarct Dementia
AIDS Dementia complex

Diagnosis

Proper differential diagnosis between the types of dementia (cortical and subcortical) will require, at the least, referral to a specialist, e.g., a geriatric internist, geriatric psychiatrist, neurologist, neuropsychologist or geropsychologist. Duration of symptoms must evident for at least six months for a diagnosis of dementia or organic brain syndrome to be made (ICD-10).

Cognitive testing

Sensitivity and specificity of common tests for dementia
Test	Sensitivity	Specificity	Reference
MMSE	71%-92%	56%-96%
3MS	83%-93.5%	85%-90%
AMTS	73%-100%	71%-100%

There exist some brief tests (5–15 minutes) that have reasonable reliability and can be used in the office or other setting to screen cognitive status. Examples of such tests include the abbreviated mental test score (AMTS), the mini mental state examination (MMSE), Modified Mini-Mental State Examination (3MS), the Cognitive Abilities Screening Instrument (CASI), and the clock drawing test. Scores must be interpreted in the context of the person's educational and other background, and the particular circumstances; for example, a person highly depressed or in great pain will not be expected to do well on many tests of mental ability.

While many tests have been studied, and some may emerge as better alternatives to the MMSE, presently the MMSE is the best studied and most commonly used.

Another approach to screening for dementia is to ask an informant (relative or other supporter) to fill out a questionnaire about the person's everyday cognitive functioning. Informant questionnaires provide complementary information to brief cognitive tests. Probably the best known questionnaire of this sort is the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). On the other hand the General Practitioner Assessment Of Cognition combines both, a patient assessment and an informant interview. It was specifically designed for the use in the primary care setting and is also available as a web-based test. It can be accessed at www.gpcog.com.au.

Further evaluation includes retesting at another date, and administration of other tests of mental function.

Laboratory tests

Routine blood tests are also usually performed to rule out treatable causes. These tests include vitamin B₁₂, folic acid, thyroid-stimulating hormone (TSH), C-reactive protein, full blood count, electrolytes, calcium, renal function, and liver enzymes. Abnormalities may suggest vitamin deficiency, infection or other problems that commonly cause confusion or disorientation in the elderly. The problem is complicated by the fact that these cause confusion more often in persons who have early dementia, so that "reversal" of such problems may ultimately only be temporary.

Testing for alcohol and other known dementia-inducing drugs may be indicated.

Imaging

A CT scan or magnetic resonance imaging (MRI scan) is commonly performed, although these modalities do not have optimal sensitivity for the diffuse metabolic changes associated with dementia in a patient that shows no gross neurological problems (such as paralysis or weakness) on neurological exam. CT or MRI may suggest normal pressure hydrocephalus, a potentially reversible cause of dementia, and can yield information relevant to other types of dementia, such as infarction (stroke) that would point at a vascular type of dementia.

The functional neuroimaging modalities of SPECT and PET are more useful in assessing long-standing cognitive dysfunction, since they have shown similar ability to diagnose dementia as a clinical exam. The ability of SPECT to differentiate the vascular cause from the Alzheimer's disease cause of dementias, appears to be superior to differentiation by clinical exam.

Recent research has established the value of PET imaging using carbon-11 Pittsburgh Compound B as a radiotracer (PIB-PET) in predictive diagnosis of various kinds of dementia, in particular Alzheimer's disease. Studies from Australia have found PIB-PET to be 86% accurate in predicting which patients with mild cognitive impairment would develop Alzheimer's disease within two years. In another study, carried out using 66 patients seen at the University of Michigan, PET studies using either PIB or another radiotracer, carbon-11 dihydrotetrabenazine (DTBZ), led to more accurate diagnosis for more than one-fourth of patients with mild cognitive impairment or mild dementia.

Prevention

Main article: Prevention of dementia

It appears that the regular moderate consumption of alcohol (beer, wine, or distilled spirits) and a Mediterranean diet may reduce risk. A study has shown a link between high blood pressure and developing dementia. The study, published in the Lancet Neurology journal July 2008, found that blood pressure lowering medication reduced dementia by 13%.

Brain-derived neurotrophic factor (BDNF) expression is associated with some dementia types.

A Canadian study found that a lifetime of bilingualism delays the onset of dementia by an average of four years when compared to monolingual patients.

Management

Except for the treatable types listed above, there is no cure to this illness. Cholinesterase inhibitors are often used early in the disease course. Cognitive and behavioral interventions may also be appropriate. Educating and providing emotional support to the caregiver (or carer) is of importance as well (see also elderly care).

Pain and dementia

See also: Assessment in nonverbal patients

As people age, they experience more health problems, and most health problems associated with aging carry a substantial burden of pain; so, between 25% and 50% of older adults experience persistent pain. Seniors with dementia experience the same prevalence of conditions likely to cause pain as seniors without dementia. Pain is often overlooked in older adults and, when screened for, often poorly assessed, especially among those with dementia. Beyond the issue of humane care, unrelieved pain has functional implications. Persistent pain can lead to decreased ambulation, depressed mood, sleep disturbances, impaired appetite and exacerbation of cognitive impairment, and pain-related interference with activity is a factor contributing to falls in the elderly.

Although persistent pain in the person with dementia is difficult to communicate, diagnose and treat, failure to address persistent pain has profound functional, psychosocial and quality of life implications for this vulnerable population. Health professionals often lack the skills and usually lack the time needed to recognize, accurately assess and adequately monitor pain in people with dementia. Family members and friends can make a valuable contribution to the care of a person with dementia by learning to recognize and assess their pain. Educational resources (such as the Understand Pain and Dementia tutorial) and observational assessment tools are available.

Medications

Acetylcholinesterase inhibitors: Tacrine (Cognex), donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon) are approved by the United States Food and Drug Administration (FDA) for treatment of dementia induced by Alzheimer's disease. They may be useful for other similar diseases causing dementia such as Parkinsons or vascular dementia.
N-methyl-D-aspartate Blockers. Memantine (Namenda) is a drug representative of this class. It can be used in combination with acetylcholinesterase inhibitors.

Off label

Amyloid deposit inhibitors: Minocycline and Clioquinoline, antibiotics, may help reduce amyloid deposits in the brains of persons with Alzheimer's disease.
Antidepressant drugs: Depression is frequently associated with dementia and generally worsens the degree of cognitive and behavioral impairment. Antidepressants effectively treat the cognitive and behavioral symptoms of depression in patients with Alzheimer's disease, but evidence for their use in other forms of dementia is weak.
Anxiolytic drugs: Many patients with dementia experience anxiety symptoms. Although benzodiazepines like diazepam (Valium) have been used for treating anxiety in other situations, they are often avoided because they may increase agitation in persons with dementia and are likely to worsen cognitive problems or are too sedating. Buspirone (Buspar) is often initially tried for mild-to-moderate anxiety. There is little evidence for the effectiveness of benzodiazepines in dementia, whereas there is evidence for the effectivess of antipsychotics (at low doses).
Selegiline, a drug used primarily in the treatment of Parkinson's disease, appears to slow the development of dementia. Selegiline is thought to act as an antioxidant, preventing free radical damage. However, it also acts as a stimulant, making it difficult to determine whether the delay in onset of dementia symptoms is due to protection from free radicals or to the general elevation of brain activity from the stimulant effect.
Antipsychotic drugs: Both typical antipsychotics (such as Haloperidol) and atypical antipsychotics such as (risperidone) increase the risk of death in dementia-associated psychosis. This means that any use of antipsychotic medication for dementia-associated psychosis is off-label and should only be considered after discussing the risks and benefits of treatment with these drugs, and after other treatment modalities have failed. In the UK around 144,000 dementia sufferers are unnecessarily prescribed antipsychotic drugs, around 2000 patients die as a result of taking the drugs each year.

Services

Adult daycare centers as well as special care units in nursing homes often provide specialized care for dementia patients. Adult daycare centers offer supervision, recreation, meals, and limited health care to participants, as well as providing respite for caregivers.

While some preliminary studies have found that music therapy may be useful in helping patients with dementia, their quality has been low and no reliable conclusions can be drawn from them.

Epidemiology

Disability-adjusted life year for Alzheimer and other dementias per 100,000 inhabitants in 2002.

no data

? 50

50-70

70-90

90-110

110-130

130-150

150-170

170-190

190-210

210-230

230-250

? 250

In a study issued by European researchers, it is estimated that about 35 million people have dementia worldwide. They said that figure is likely to double every 20 years, to nearly 66 million in 2030 and 115 million in 2050.

External links

BBC Headroom: Living with Dementia
The Dementia Centre - Information provided by PSS (Personal Services Society). Provides information and support to people with dementia, their carers, and health professionals.
Alzheimer's Research Trust - What is dementia? - Information produced by the Alzheimer's Research Trust including statistics.
Alzheimer's Society - About dementia - Information produced by the Alzheimer's Society including factsheets and support.
The Dementia Services Development Centre, University of Stirling
Dementia tutorial for U.K. practitioners by the Alzheimer's Society
Understanding Dementia: a primer of diagnosis and management
AlzOnline - AlzOnline provides education, information, and support to persons caring for someone with Alzheimer's disease or a related memory problem.
Medicinenet
Understand Pain and Dementia tutorial from the Occupational Therapy Department at the University of Alberta
Concise Guidelines to Better Practice The Assessment of Pain in Older Person - British Pain Society (2007)

Dementia at GPnotebook
Dementia at eMedicineHealth
Merck Geriatrics 5-40a

ABOUT CONGESTIVE HEART FAILURE

Heart failure
The major signs and symptoms of heart failure.

Heart failure (HF) often called congestive heart failure (CHF) is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition is diagnosed with echocardiography and blood tests. Treatment commonly consists of lifestyle measures (such as smoking cessation, light exercise including breathing protocols, decreased salt intake and other dietary changes) and medications, and sometimes devices or even surgery.

Common causes of heart failure include myocardial infarction and other forms of ischemic heart disease, hypertension, valvular heart disease, and cardiomyopathy. The term "heart failure" is sometimes incorrectly used to describe other cardiac-related illnesses, such as myocardial infarction (heart attack) or cardiac arrest.

Heart failure is a common, costly, disabling, and potentially deadly condition. In developed countries, around 2% of adults suffer from heart failure, but in those over the age of 65, this increases to 6–10%.

Terminology

Heart failure is a global term for the physiological state in which cardiac output is insufficient in meeting the needs of the body and lungs. Often termed "congestive heart failure" or CHF, this is most commonly caused when cardiac output is low and the body becomes congested with fluid.

It may also occur when the body's requirements for oxygen and nutrients are increased and the demand outstrips what the heart can provide, (termed "high output cardiac failure"). This can occur from severe anemia, Gram negative septicaemia, beriberi (vitamin B₁/thiamine deficiency), thyrotoxicosis, Paget's disease, arteriovenous fistulae, or arteriovenous malformations.

Fluid overload is a common problem for people with heart failure but is not synonymous with it. Patients with treated heart failure will often be euvolaemic (a term for normal fluid status), or more rarely, dehydrated.

Medical professionals use the words "acute" to mean of rapid onset and "chronic" of long duration. Chronic heart failure is therefore a long term situation, usually with stable treated symptomatology.

Acute decompensated heart failure is a term used to describe exacerbated or decompensated heart failure, referring to episodes in which a patient can be characterized as having a change in heart failure signs and symptoms resulting in a need for urgent therapy or hospitalization.

There are several terms which are closely related to heart failure, and may be the cause of heart failure, but should not be confused with it:

Cardiac arrest and asystole refer to situations in which there is no cardiac output at all. Without urgent treatment these result in sudden death.
Myocardial infarction ("Heart attack") refers to heart muscle damage due to insufficient blood supply, usually as a result of a blocked coronary artery.
Cardiomyopathy refers specifically to problems within the heart muscle, and these problems usually result in heart failure. Ischemic cardiomyopathy implies that the cause of muscle damage is coronary artery disease. Dilated cardiomyopathy implies that the muscle damage has resulted in enlargement of the heart. Hypertrophic cardiomyopathy involves enlargement and thickening of the heart muscle.

Classification

There are many different ways to categorize heart failure, including:

the side of the heart involved, (left heart failure versus right heart failure) Left heart failure compromises aortic flow to the body and brain. Right heart failure compromises pulmonic flow to the lungs. Mixed presentations are common, especially when the cardiac septum is involved.
whether the abnormality is due to insufficient contraction and/or relaxation of the heart (systolic dysfunction vs. diastolic dysfunction)
whether the problem is primarily increased venous back pressure (behind) the heart Afterload, or failure to supply adequate arterial perfusion (in front of) the heart Preload (backward vs. forward failure)
whether the abnormality is due to low cardiac output with high systemic vascular resistance or high cardiac output with low vascular resistance (low-output heart failure vs. high-output heart failure)
the degree of functional impairment conferred by the abnormality (as in the NYHA functional classification)
the degree of coexisting illness: i.e. heart failure/systemic hypertension, heart failure/pulmonary hypertension, heart failure/diabetes, heart failure/renal failure, etc.

Functional classification generally relies on the New York Heart Association Functional Classification. The classes (I-IV) are:

Class I: no limitation is experienced in any activities; there are no symptoms from ordinary activities.
Class II: slight, mild limitation of activity; the patient is comfortable at rest or with mild exertion.
Class III: marked limitation of any activity; the patient is comfortable only at rest.
Class IV: any physical activity brings on discomfort and symptoms occur at rest.

This score documents severity of symptoms, and can be used to assess response to treatment. While its use is widespread, the NYHA score is not very reproducible and doesn't reliably predict the walking distance or exercise tolerance on formal testing.

In its 2001 guidelines the American College of Cardiology/American Heart Association working group introduced four stages of heart failure:

Stage A: Patients at high risk for developing HF in the future but no functional or structural heart disorder;
Stage B: a structural heart disorder but no symptoms at any stage;
Stage C: previous or current symptoms of heart failure in the context of an underlying structural heart problem, but managed with medical treatment;
Stage D: advanced disease requiring hospital-based support, a heart transplant or palliative care.

The ACC staging system is useful in that Stage A encompasses "pre-heart failure" - a stage where intervention with treatment can presumably prevent progression to overt symptoms. ACC stage A does not have a corresponding NYHA class. ACC Stage B would correspond to NYHA Class I. ACC Stage C corresponds to NYHA Class II and III, while ACC Stage D overlaps with NYHA Class IV.

Signs and symptoms

A man with congestive heart failure and marked jugular venous distension. External jugular vein marked by an arrow.

Signs

Left-sided failure

Common respiratory signs are tachypnea (increased rate of breathing) and increased work of breathing (non-specific signs of respiratory distress). Rales or crackles, heard initially in the lung bases, and when severe, throughout the lung fields suggest the development of pulmonary edema (fluid in the alveoli). Cyanosis which suggests severe hypoxemia, is a late sign of extremely severe pulmonary edema.

Additional signs indicating left ventricular failure include a laterally displaced apex beat (which occurs if the heart is enlarged) and a gallop rhythm (additional heart sounds) may be heard as a marker of increased blood flow, or increased intra-cardiac pressure. Heart murmurs may indicate the presence of valvular heart disease, either as a cause (e.g. aortic stenosis) or as a result (e.g., mitral regurgitation) of the heart failure.

Right-sided failure

Physical examination can reveal pitting peripheral edema, ascites, and hepatomegaly. Jugular venous pressure is frequently assessed as a marker of fluid status, which can be accentuated by the hepatojugular reflux. If the right ventricular pressure is increased, a parasternal heave may be present, signifying the compensatory increase in contraction strength.

Biventricular failure

Dullness of the lung fields to finger percussion and reduced breath sounds at the bases of the lung may suggest the development of a pleural effusion (fluid collection in between the lung and the chest wall). Though it can occur in isolated left- or right-sided heart failure, it is more common in biventricular failure because pleural veins drain both into the systemic and pulmonary venous system. When unilateral, effusions are often right sided.

Symptoms

Heart failure symptoms are traditionally and somewhat arbitrarily divided into "left" and "right" sided, recognizing that the left and right ventricles of the heart supply different portions of the circulation. However, heart failure is not exclusively backward failure (in the part of the circulation which drains to the ventricle).

There are several other exceptions to a simple left-right division of heart failure symptoms. Left sided forward failure overlaps with right sided backward failure. Additionally, the most common cause of right-sided heart failure is left-sided heart failure. The result is that patients commonly present with both sets of signs and symptoms.

Left-sided failure

Backward failure of the left ventricle causes congestion of the pulmonary vasculature, and so the symptoms are predominantly respiratory in nature. Backward failure can be subdivided into failure of the left atrium, the left ventricle or both within the left circuit. The patient will have dyspnea (shortness of breath) on exertion (dyspnée d'effort) and in severe cases, dyspnea at rest. Increasing breathlessness on lying flat, called orthopnea, occurs. It is often measured in the number of pillows required to lie comfortably, and in severe cases, the patient may resort to sleeping while sitting up. Another symptom of heart failure is paroxysmal nocturnal dyspnea a sudden nighttime attack of severe breathlessness, usually several hours after going to sleep. Easy fatigueability and exercise intolerance are also common complaints related to respiratory compromise.

"Cardiac asthma" or wheezing may occur.

Compromise of left ventricular forward function may result in symptoms of poor systemic circulation such as dizziness, confusion and cool extremities at rest.

Right-sided failure

Backward failure of the right ventricle leads to congestion of systemic capillaries. This generates excess fluid accumulation in the body. This causes swelling under the skin (termed peripheral edema or anasarca) and usually affects the dependent parts of the body first (causing foot and ankle swelling in people who are standing up, and sacral edema in people who are predominantly lying down). Nocturia (frequent nighttime urination) may occur when fluid from the legs is returned to the bloodstream while lying down at night. In progressively severe cases, ascites (fluid accumulation in the abdominal cavity causing swelling) and hepatomegaly (enlargement of the liver) may develop. Significant liver congestion may result in impaired liver function, and jaundice and even coagulopathy (problems of decreased blood clotting) may occur.

Causes

Chronic heart failure

The predominance of causes of heart failure are difficult to analyze due to challenges in diagnosis, differences in populations, and changing prevalence of causes with age.

A 19 year study of 13000 healthy adults in the United States (the National Health and Nutrition Examination Survey (NHANES I) found the following causes ranked by Population Attributable Risk score:

Ischaemic heart disease 62%
Cigarette smoking 16%
Hypertension (high blood pressure)10%
Obesity 8%
Diabetes 3%
Valvular heart disease 2% (much higher in older populations)

An Italian registry of over 6200 patients with heart failure showed the following underlying causes:

Ischaemic heart disease 40%
Dilated cardiomyopathy 32%
Valvular heart disease 12%
Hypertension 11%
Other 5%

Rarer causes of heart failure include:

Viral myocarditis (an infection of the heart muscle)
Infiltrations of the muscle such as amyloidosis
HIV cardiomyopathy (caused by human immunodeficiency virus)
Connective tissue diseases such as systemic lupus erythematosus
Abuse of drugs such as alcohol and cocaine
Pharmaceutical drugs such as chemotherapeutic agents
Arrhythmias

Obstructive sleep apnea a condition of sleep disordered breathing overlaps with obesity, hypertension, and diabetes and is regarded as an independent cause of heart failure.

Acute decompensated heart failure

Main article: Acute decompensated heart failure

Chronic stable heart failure may easily decompensate. This most commonly results from an intercurrent illness (such as pneumonia), myocardial infarction (a heart attack), arrhythmias, uncontrolled hypertension, or a patient's failure to maintain a fluid restriction, diet, or medication. Other well recognized precipitating factors include anemia and hyperthyroidism which place additional strain on the heart muscle. Excessive fluid or salt intake, and medication that causes fluid retention such as NSAIDs and thiazolidinediones, may also precipitate decompensation.

Pathophysiology

Heart failure is caused by any condition which reduces the efficiency of the myocardium, or heart muscle, through damage or overloading. As such, it can be caused by as diverse an array of conditions as myocardial infarction (in which the heart muscle is starved of oxygen and dies), hypertension (which increases the force of contraction needed to pump blood) and amyloidosis (in which protein is deposited in the heart muscle, causing it to stiffen). Over time these increases in workload will produce changes to the heart itself:

Reduced force of contraction, due to overloading of the ventricle. In health, increased filling of the ventricle results in increased force of contraction (by the Frank–Starling law of the heart) and thus a rise in cardiac output. In heart failure this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This is due to reduced ability to cross-link actin and myosin filaments in over-stretched heart muscle.
A reduced stroke volume, as a result of a failure of systole, diastole or both. Increased end systolic volume is usually caused by reduced contractility. Decreased end diastolic volume results from impaired ventricular filling – as occurs when the compliance of the ventricle falls (i.e. when the walls stiffen).
Reduced spare capacity. As the heart works harder to meet normal metabolic demands, the amount cardiac output can increase in times of increased oxygen demand (e.g. exercise) is reduced. This contributes to the exercise intolerance commonly seen in heart failure. This translates to the loss of one's cardiac reserve. The cardiac reserve refers to the ability of the heart to work harder during exercise or strenuous activity. Since the heart has to work harder to meet the normal metabolic demands, it is incapable of meeting the metabolic demands of the body during exercise.
Increased heart rate, stimulated by increased sympathetic activity in order to maintain cardiac output. Initially, this helps compensate for heart failure by maintaining blood pressure and perfusion, but places further strain on the myocardium, increasing coronary perfusion requirements, which can lead to worsening of ischemic heart disease. Sympathetic activity may also cause potentially fatal arrhythmias.
Hypertrophy (an increase in physical size) of the myocardium, caused by the terminally differentiated heart muscle fibres increasing in size in an attempt to improve contractility. This may contribute to the increased stiffness and decreased ability to relax during diastole.
Enlargement of the ventricles, contributing to the enlargement and spherical shape of the failing heart. The increase in ventricular volume also causes a reduction in stroke volume due to mechanical and contractile inefficiency.

The general effect is one of reduced cardiac output and increased strain on the heart. This increases the risk of cardiac arrest (specifically due to ventricular dysrhythmias), and reduces blood supply to the rest of the body. In chronic disease the reduced cardiac output causes a number of changes in the rest of the body, some of which are physiological compensations, some of which are part of the disease process:

Arterial blood pressure falls. This destimulates baroreceptors in the carotid sinus and aortic arch which link to the nucleus tractus solitarius. This center in the brain increases sympathetic activity, releasing catecholamines into the blood stream. Binding to alpha-1 receptors results in systemic arterial vasoconstriction. This helps restore blood pressure but also increases the total peripheral resistance, increasing the workload of the heart. Binding to beta-1 receptors in the myocardium increases the heart rate and make contractions more forceful, in an attempt to increase cardiac output. This also, however, increases the amount of work the heart has to perform.
Increased sympathetic stimulation also causes the hypothalamus to secrete vasopressin (also known as antidiuretic hormone or ADH), which causes fluid retention at the kidneys. This increases the blood volume and blood pressure.
Reduced perfusion (blood flow) to the kidneys stimulates the release of renin – an enzyme which catalyses the production of the potent vasopressor angiotensin. Angiotensin and its metabolites cause further vasocontriction, and stimulate increased secretion of the steroid aldosterone from the adrenal glands. This promotes salt and fluid retention at the kidneys, also increasing the blood volume.
The chronically high levels of circulating neuroendocrine hormones such as catecholamines, renin, angiotensin, and aldosterone affects the myocardium directly, causing structural remodelling of the heart over the long term. Many of these remodelling effects seem to be mediated by transforming growth factor beta (TGF-beta), which is a common downstream target of the signal transduction cascade initiated by catecholamines and angiotensin II, and also by epidermal growth factor (EGF), which is a target of the signaling pathway activated by aldosterone
Reduced perfusion of skeletal muscle causes atrophy of the muscle fibres. This can result in weakness, increased fatigueability and decreased peak strength - all contributing to exercise intolerance.

The increased peripheral resistance and greater blood volume place further strain on the heart and accelerates the process of damage to the myocardium. Vasoconstriction and fluid retention produce an increased hydrostatic pressure in the capillaries. This shifts the balance of forces in favour of interstitial fluid formation as the increased pressure forces additional fluid out of the blood, into the tissue. This results in edema (fluid build-up) in the tissues. In right-sided heart failure this commonly starts in the ankles where venous pressure is high due to the effects of gravity (although if the patient is bed-ridden, fluid accumulation may begin in the sacral region.) It may also occur in the abdominal cavity, where the fluid build-up is called ascites. In left-sided heart failure edema can occur in the lungs - this is called cardiogenic pulmonary edema. This reduces spare capacity for ventilation, causes stiffening of the lungs and reduces the efficiency of gas exchange by increasing the distance between the air and the blood. The consequences of this are shortness of breath, orthopnea and paroxysmal nocturnal dyspnea.

The symptoms of heart failure are largely determined by which side of the heart fails. The left side pumps blood into the systemic circulation, whilst the right side pumps blood into the pulmonary circulation. Whilst left-sided heart failure will reduce cardiac output to the systemic circulation, the initial symptoms often manifest due to effects on the pulmonary circulation. In systolic dysfunction, the ejection fraction is decreased, leaving an abnormally elevated volume of blood in the left ventricle. In diastolic dysfunction, end-diastolic ventricular pressure will be high. This increase in volume or pressure backs up to the left atrium and then to the pulmonary veins. Increased volume or pressure in the pulmonary veins impairs the normal drainage of the alveoli and favors the flow of fluid from the capillaries to the lung parenchyma, causing pulmonary edema. This impairs gas exchange. Thus, left-sided heart failure often presents with respiratory symptoms: shortness of breath, orthopnea and paroxysmal nocturnal dyspnea.

In severe cardiomyopathy, the effects of decreased cardiac output and poor perfusion become more apparent, and patients will manifest with cold and clammy extremities, cyanosis, claudication, generalized weakness, dizziness, and syncope

The resultant hypoxia caused by pulmonary edema causes vasoconstriction in the pulmonary circulation, which results in pulmonary hypertension. Since the right ventricle generates far lower pressures than the left ventricle (approximately 20 mmHg versus around 120 mmHg, respectively, in the healthy individual) but nonetheless generates cardiac output exactly equal to the left ventricle, this means that a small increase in pulmonary vascular resistance causes a large increase in amount of work the right ventricle must perform. However, the main mechanism by which left-sided heart failure causes right-sided heart failure is actually not well understood. Some theories invoke mechanisms that are mediated by neurohormonal activation. Mechanical effects may also contribute. As the left ventricle distends, the intraventricular septum bows into the right ventricle, decreasing the capacity of the right ventricle.

Systolic dysfunction

Heart failure caused by systolic dysfunction is more readily recognized. It can be simplistically described as failure of the pump function of the heart. It is characterized by a decreased ejection fraction (less than 45%). The strength of ventricular contraction is attenuated and inadequate for creating an adequate stroke volume, resulting in inadequate cardiac output. In general, this is caused by dysfunction or destruction of cardiac myocytes or their molecular components. In congenital diseases such as Duchenne muscular dystrophy, the molecular structure of individual myocytes is affected. Myocytes and their components can be damaged by inflammation (such as in myocarditis) or by infiltration (such as in amyloidosis). Toxins and pharmacological agents (such as ethanol, cocaine, and amphetamines) cause intracellular damage and oxidative stress. The most common mechanism of damage is ischemia causing infarction and scar formation. After myocardial infarction, dead myocytes are replaced by scar tissue, deleteriously affecting the function of the myocardium. On echocardiogram, this is manifest by abnormal or absent wall motion.

Because the ventricle is inadequately emptied, ventricular end-diastolic pressure and volumes increase. This is transmitted to the atrium. On the left side of the heart, the increased pressure is transmitted to the pulmonary vasculature, and the resultant hydrostatic pressure favors extravassation of fluid into the lung parenchyma, causing pulmonary edema. On the right side of the heart, the increased pressure is transmitted to the systemic venous circulation and systemic capillary beds, favoring extravassation of fluid into the tissues of target organs and extremities, resulting in dependent peripheral edema.

Diastolic dysfunction

Heart failure caused by diastolic dysfunction is generally described as the failure of the ventricle to adequately relax and typically denotes a stiffer ventricular wall. This causes inadequate filling of the ventricle, and therefore results in an inadequate stroke volume. The failure of ventricular relaxation also results in elevated end-diastolic pressures, and the end result is identical to the case of systolic dysfunction (pulmonary edema in left heart failure, peripheral edema in right heart failure.)

Diastolic dysfunction can be caused by processes similar to those that cause systolic dysfunction, particularly causes that affect cardiac remodeling.

Diastolic dysfunction may not manifest itself except in physiologic extremes if systolic function is preserved. The patient may be completely asymptomatic at rest. However, they are exquisitely sensitive to increases in heart rate, and sudden bouts of tachycardia (which can be caused simply by physiological responses to exertion, fever, or dehydration, or by pathological tachyarrhythmias such as atrial fibrillation with rapid ventricular response) may result in flash pulmonary edema. Adequate rate control (usually with a pharmacological agent that slows down AV conduction such as a calcium channel blocker or a beta-blocker) is therefore key to preventing decompensation.

Left ventricular diastolic function can be determined through echocardiography by measurement of various parameters such as the E/A ratio (early-to-atrial left ventricular filling ratio), the E (early left ventricular filling) deceleration time, and the isovolumic relaxation time.

Diagnosis

Acute pulmonary edema. Note enlarged heart size, apical vascular redistribution ( circle ), and small bilateral pleural effusions ( arrow ).

No system of diagnostic criteria has been agreed as the gold standard for heart failure. Commonly used systems are the "Framingham criteria" (derived from the Framingham Heart Study), the "Boston criteria", the "Duke criteria", and (in the setting of acute myocardial infarction) the "Killip class".

Imaging

Echocardiography is commonly used to support a clinical diagnosis of heart failure. This modality uses ultrasound to determine the stroke volume (SV, the amount of blood in the heart that exits the ventricles with each beat), the end-diastolic volume (EDV, the total amount of blood at the end of diastole), and the SV in proportion to the EDV, a value known as the ejection fraction (EF). In pediatrics, the shortening fraction is the preferred measure of systolic function. Normally, the EF should be between 50% and 70%; in systolic heart failure, it drops below 40%. Echocardiography can also identify valvular heart disease and assess the state of the pericardium (the connective tissue sac surrounding the heart). Echocardiography may also aid in deciding what treatments will help the patient, such as medication, insertion of an implantable cardioverter-defibrillator or cardiac resynchronization therapy. Echocardiography can also help determine if acute myocardial ischemia is the precipitating cause, and may manifest as regional wall motion abnormalities on echo.

Chest X-rays are frequently used to aid in the diagnosis of CHF. In the compensated patient, this may show cardiomegaly (visible enlargement of the heart), quantified as the cardiothoracic ratio (proportion of the heart size to the chest). In left ventricular failure, there may be evidence of vascular redistribution ("upper lobe blood diversion" or "cephalization"), Kerley lines, cuffing of the areas around the bronchi, and interstitial edema.

Electrophysiology

An electrocardiogram (ECG/EKG) may be used to identify arrhythmias, ischemic heart disease, right and left ventricular hypertrophy, and presence of conduction delay or abnormalities (e.g. left bundle branch block). Although these findings are not specific to the diagnosis of heart failure a normal ECG virtually excludes left ventricular systolic dysfunction.

Blood tests

Blood tests routinely performed include electrolytes (sodium, potassium), measures of renal function, liver function tests, thyroid function tests, a complete blood count, and often C-reactive protein if infection is suspected. An elevated B-type natriuretic peptide (BNP) is a specific test indicative of heart failure. Additionally, BNP can be used to differentiate between causes of dyspnea due to heart failure from other causes of dyspnea. If myocardial infarction is suspected, various cardiac markers may be used.

According to a meta-analysis comparing BNP and N-terminal pro-BNP (NTproBNP) in the diagnosis of heart failure, BNP is a better indicator for heart failure and left ventricular systolic dysfunction. In groups of symptomatic patients, a diagnostic odds ratio of 27 for BNP compares with a sensitivity of 85% and specificity of 84% in detecting heart failure.

Angiography

Heart failure may be the result of coronary artery disease, and its prognosis depends in part on the ability of the coronary arteries to supply blood to the myocardium (heart muscle). As a result, coronary catheterization may be used to identify possibilities for revascularisation through percutaneous coronary intervention or bypass surgery.

Monitoring

Various measures are often used to assess the progress of patients being treated for heart failure. These include fluid balance (calculation of fluid intake and excretion), monitoring body weight (which in the shorter term reflects fluid shifts).

Algorithms

There are various algorithms for the diagnosis of heart failure. For example, the algorithm used by the Framingham Heart Study adds together criteria mainly from physical examination. In contrast, the more extensive algorithm by the European Society of Cardiology (ESC) weights the difference between supporting and opposing parameters from the medical history, physical examination, further medical tests as well as response to therapy.

Framingham criteria

By the Framingham criteria, diagnosis of congestive heart failure (heart failure with impaired pumping capability) requires the simultaneous presence of at least 2 of the following major criteria or 1 major criterion in conjunction with 2 of the following minor criteria:

Major criteria:

Cardiomegaly on chest radiography
S3 gallop (a third heart sound)
Acute pulmonary edema
Paroxysmal nocturnal dyspnea
Crackles on lung auscultation
Central venous pressure of more than 16 cm H2O at the right atrium
Jugular vein distension
Positive abdominojugular test
Weight loss of more than 4.5 kg in 5 days in response to treatment (sometimes classified as a minor criterium)

Minor criteria:

Tachycardia of more than 120 beats per minute
Nocturnal cough
Dyspnea on ordinary exertion
Pleural effusion
Decrease in vital capacity by one third from maximum recorded
Hepatomegaly
Bilateral ankle edema

Minor criteria are acceptable only if they can not be attributed to another medical condition such as pulmonary hypertension, chronic lung disease, cirrhosis, ascites, or the nephrotic syndrome. The Framingham Heart Study criteria are 100% sensitive and 78% specific for identifying persons with definite congestive heart failure.

ESC algorithm

The ESC algorithm weights the following parameters in establishing the diagnosis of heart failure:

Influence Parameter	Supports if present	Opposes if normal or absent
Influence Parameter	+ - to some degree ++ - to intermediate degree +++ - to high degree
Compatible symptoms	++	++
Compatible signs	++	+
Cardiac dysfunction on echocardiography	+++	+++
Response of symptoms or signs to therapy	+++	++
ECG
Normal		++
Abnormal	++	+
Dysrhythmia	+++	+
Laboratory
BNP > 400 pg/mL and/or NT-proBNP > 2000 pg/mL	+++	+
BNP < 100 pg/mL and NT-proBNP < 400 pg/mL	+	+++
Hyponatraemia	+	+
Renal dysfunction	+	+
Mild elevations of troponin	+	+
Chest X-ray
Pulmonary congestion	+++	+
Reduced exercise capacity	+++	++
Abnormal pulmonary function tests	+	+
Abnormal haemodynamics at rest	+++	++

Management

Main article: Management of heart failure

Treatment focuses on improving the symptoms and preventing the progression of the disease. Reversible causes of the heart failure also need to be addressed: (e.g. infection, alcohol ingestion, anemia, thyrotoxicosis, arrhythmia, hypertension). Treatments include lifestyle and pharmacological modalities.

Acute decompensation

Main article: Acute decompensated heart failure

In acute decompensated heart failure (ADHF), the immediate goal is to re-establish adequate perfusion and oxygen delivery to end organs. This entails ensuring that airway, breathing, and circulation are adequate. Immediated treatments usually involve some combination of vasodilators such as nitroglycerin, diuretics such as furosemide, and possibly non invasive positive pressure ventilation (NIPPV).

Chronic management

The goal is to prevent the development of acute decompensated heart failure, to counteract the deleterious effects of cardiac remodeling, and to minimize the symptoms that the patient suffers. First-line therapy for all heart failure patients is angiotensin-converting enzyme (ACE) inhibition. ACE inhibitors (i.e., enalapril, captopril, lisinopril, ramipril) improve survival and quality of life in heart failure patients, and have been shown to reduce mortality in patients with left ventricular dysfunction in numerous randomized trials. In addition to pharmacologic agents (oral loop diuretics, beta-blockers, ACE inhibitors or angiotensin receptor blockers, vasodilators, and in severe cardiomyopathy aldosterone receptor antagonists), behavioral modification should be pursued, specifically with regards to dietary guidelines regarding salt and fluid intake. Exercise should be encouraged as tolerated, as sufficient conditioning can significantly improve quality-of-life.

In patients with severe cardiomyopathy, implantation of an automatic implantable cardioverter defibrillator (AICD) should be considered. A select population will also probably benefit from ventricular resynchronization.

In select cases, cardiac transplantation can be considered. While this may resolve the problems associated with heart failure, the patient generally must remain on an immunosuppressive regimen to prevent rejection, which has its own significant downsides.

Home dobutamine and milrinone

These two medications are both ionotropes with sympathomimetic effect. Both can be used in severe heart failure, generally in patients who require frequent exacerbations with hospitalization and/or refractory symptoms. While both medications have proven to improve symptoms, both also increase the risk of sudden cardiac death, and the research suggests an increased mortality rate for patients who are started on these medications. Extensive counseling about symptom management vs. risk of earlier death needs to be undertaken before starting the medication.

Palliative care

Patients with CHF often have significant symptoms, such as shortness of breath and chest pain. Both palliative care and cardiology are trying to get palliative care involved earlier in the course of patients with heart failure, and some would argue any patient with NYHA class III CHF should have a palliative care referral. Palliative care can not only provide symptom management, but also assist with advanced care planning, goals of care in the case of a significant decline, and making sure the patient has a medical power of attorney and discussed his or her wishes with this individual.

Hospice

Without transplantation, heart failure caused by ischemic heart disease is not reversible, and cardiac function typically deteriorates with time. In particular, diastolic function worsens as a function of age even in individuals without ischemic heart disease. The majority of non-ischemic cardiomyopathis are also not reversible, especially when they have gotten to stage IV. The growing number of patients with Stage IV heart failure (intractable symptoms of fatigue, shortness of breath or chest pain at rest despite optimal medical therapy) should be considered for palliative care or hospice, according to American College of Cardiology/American Heart Association guidelines.

Prognosis

Prognosis in heart failure can be assessed in multiple ways including clinical prediction rules and cardiopulmonary exercise testing. Clinical prediction rules use a composite of clinical factors such as lab tests and blood pressure to estimate prognosis. Among several clinical prediction rules for prognosing acute heart failure, the 'EFFECT rule' slightly outperformed other rules in stratifying patients and identifying those at low risk of death during hospitalization or within 30 days. Easy methods for identifying low risk patients are:

ADHERE Tree rule indicates that patients with blood urea nitrogen < 43 mg/dl and systolic blood pressure at least 115 mm Hg have less than 10% chance of inpatient death or complications.
BWH rule indicates that patients with systolic blood pressure over 90 mm Hg, respiratory rate of 30 or less breaths per minute, serum sodium over 135 mmol/L, no new ST-T wave changes have less than 10% chance of inpatient death or complications.

A very important method for assessing prognosis in advanced heart failure patients is cardiopulmonary exercise testing (CPX testing). CPX testing is usually required prior to heart transplantation as an indicator of prognosis. Cardiopulmonary exercise testing involves measurement of exhaled oxygen and carbon dioxide during exercise. The peak oxygen consumption (VO2 max) is used as an indicator of prognosis. As a general rule, a VO2 max less than 12-14 cc/kg/min indicates a poor survival and suggests that the patient may be a candidate for a heart transplant. Patients with a VO2 max<10 cc/kg/min have clearly poorer prognosis. The most recent International Society for Heart and Lung Transplantation (ISHLT) guidelines also suggest two other parameters that can be used for evaluation of prognosis in advanced heart failure, the heart failure survival score and the use of a criterion of VE/VCO2 slope > 35 from the CPX test. The heart failure survival score is a score calculated using a combination of clinical predictors and the VO2 max from the cardiopulmonary exercise test.

Epidemiology

Mostly as a result of the costs of hospitalization, it is associated with a high health expenditure; costs have been estimated to amount to 2% of the total budget of the National Health Service in the United Kingdom, and more than $35 billion in the United States. Heart failure is associated with significantly reduced physical and mental health, resulting in a markedly decreased quality of life. With the exception of heart failure caused by reversible conditions, the condition usually worsens with time. Although some people survive many years, progressive disease is associated with an overall annual mortality rate of 10%.

Heart failure is the leading cause of hospitalization in people older than 65. In developed countries, the mean age of patients with heart failure is 75 years old. In developing countries, two to three percent of the population suffers from heart failure, but in those 70 to 80 years old, it occurs in 20—30 percent.

Heart failure affects close to 5 million people in the USA and each year close to 500,000 new cases are diagnosed. What is of more concern is that more than 50% of patients seek re-admission within 6 months after treatment and the average duration of hospital stay is 6 days.

In tropical countries, the most common cause of HF is valvular heart disease or some type of cardiomyopathy. Moreover as underdeveloped countries become more affluent, there has also been an increase in diabetes, hypertension and obesity which has resulted in heart failure.

In USA, HF is much higher in African Americans, Hispanics, Native Americans and recent immigrants from the eastern bloc countries like Russia. This high prevalence in these ethnic populations has been linked to high incidence of diabetes and hypertension. In many new immigrants to the USA the high prevalence of heart failure has largely been attributed to lack of preventive health care or substandard treatment.

Sex

Men have a higher incidence of heart failure, but the overall prevalence rate is similar in both sexes, since women survive longer after the onset of heart failure. Women tend to be older when diagnosed with heart failure (after menopause), they are more likely than men to have diastolic dysfunction, and seem to experience a lower overall quality of life than men after diagnosis.

Race

New information suggests that elements of heart failure in African Americans and Caucasians may be different and therapy for heart failure has different efficacies depending on racial, ethnic, and genetic backgrounds.

Age

Heart failure basically means that the heart muscles have become weak and do not function as normal. Heart failure is a progressive medical disorder. As the heart gets weaker, symptoms and signs become prominent. Heart failure can affect the entire heart or only the right or left side. In the majority of cases, both sides of the heart are affected. HF can occur at any age depending on the cause. In general heart failure does increase with age.

External links

American Heart Association's Heart Failure web site - information and resources for treating and living with heart failure.
Heart Failure Matters – patient information website of the Heart Failure Association of the European Society of Cardiology

Cities in Los Angeles County

Los Angeles County (incorporated as the County of Los Angeles) is a county in the U.S. state of California. As of 2010 U.S. Census, the county had a population of 9,818,605, making it the most populous county in the United States. Los Angeles County alone is more populous than 42 individual U.S. states. The county seat is the city of Los Angeles, the largest city in California and the second-largest city in the United States (after New York City).

The county is home to over a quarter of all California residents. One of the most diverse counties in the country, it holds most of the principal cities composing the Los Angeles metropolitan area, and is the core of the five counties that make up the Greater Los Angeles Area.

History

Los Angeles County was one of the original counties of California, created at the time of statehood in 1850. The county's large area included parts of what is now Kern County, San Bernardino County, Riverside County and Orange County. These parts of the county's territory were given to San Bernardino County in 1853, to Kern County in 1866 and to Orange County in 1889. In 1893, part of San Bernardino County became Riverside County.

Geography

According to the 2000 census, the county has a total area of 4,752.32 square miles (12,308.5 km²), of which 4,060.87 square miles (10,517.6 km²) (or 85.45%) is land and 691.45 square miles (1,790.8 km²) (or 14.55%) is water. Los Angeles County borders 70 miles (110 km) of coast on the Pacific Ocean and encompasses towering mountain ranges, deep valleys, forests, islands, lakes, rivers, and desert. The Los Angeles River, Rio Hondo, the San Gabriel River and the Santa Clara River flow in Los Angeles County, while the primary mountain ranges are the Santa Monica Mountains and the San Gabriel Mountains. The western extent of the Mojave Desert begins in the Antelope Valley, in the northeastern part of the county. Most of the population of Los Angeles County is located in the south and southwest, with major population centers in the Los Angeles Basin, San Fernando Valley and San Gabriel Valley. Other population centers are found in the Santa Clarita Valley, Crescenta Valley and Antelope Valley.

Major divisions of the county

Cities

There are 88 incorporated cities in Los Angeles County. The most populous are as follows:

Unincorporated areas in Los Angeles County

Despite the large number of incorporated cities, most of the area of the county is unincorporated, and falls directly under the county government's jurisdiction. With no city government, residents of these areas must petition the appropriate member of the Board of Supervisors when they have a grievance about the quality of local services.

Census-designated places

Communities not census-designated

Adjacent counties

National protected areas

Transportation infrastructure

Roads

The county has an extensive freeway network of legendary size and complexity, which is maintained by Caltrans and patrolled by the California Highway Patrol. It also has a vast urban and suburban street network, most of which is maintained by city governments. The county and most cities generally do a decent job of maintaining and cleaning streets. For more information about the primary exception, see the Transportation in Los Angeles article.

Both the freeways and streets are notorious for severe traffic congestion, and the area's freeway-to-freeway interchanges regularly rank among the top 10 most congested points in the country.

In addition to Metro Bus service, numerous cities within the county also operate their own bus companies and shuttle lines.

Major highways

Air

Train

Los Angeles is a major freight railroad transportation center, largely due to the large volumes of freight moving in and out of the county's port facilities. The ports are connected to the downtown rail yards and to the main lines of Union Pacific and Burlington Northern Santa Fe headed east via a grade-separated, freight rail corridor known as the Alameda Corridor.

Amtrak has the following intercity Amtrak service at Union Station in the city of Los Angeles.

Union Station is also the primary hub for Metrolink commuter rail, which serves much of the Greater Los Angeles Area.

Sea

The county's two main seaports are the Port of Los Angeles and the Port of Long Beach. Together they handle over a quarter of all container traffic entering the United States, making the complex the largest and most important port in the country, and the third-largest port in the world by shipping volume.

The Port of Los Angeles is the largest cruise ship center on the West Coast, handling more than 1 million passengers annually.

The Port of Long Beach is home to the Sea Launch program, which uses a floating launch platform to insert payloads into orbits that would be difficult to attain from existing land-based launch sites.

Economy

Los Angeles County is commonly associated with the entertainment industry; all six major film studios—Paramount Pictures, 20th Century Fox, Sony, Warner Bros., Universal Pictures, and Walt Disney Studios—are located within the county. Beyond motion picture and television program production, other major industries of Los Angeles County are international trade supported by the Port of Los Angeles and the Port of Long Beach, music recording and production, aerospace, and professional services such as law and medicine.

The following major companies have headquarters in Los Angeles County cities not adjacent to the city of Los Angeles:

Demographics

2010

2000

As of the census of 2000, there were 9,519,338 people, 3,133,774 households, and 2,137,233 families residing in the county. The population density was 2,344 people per square mile (905/km²). There were 3,270,909 housing units at an average density of 806 per square mile (311/km²). The racial makeup of the county is 48.7% White 11.0% African American, 0.8% Native American, 10.0% Asian, 0.3% Pacific Islander, 23.5% from other races, and 4.9% from two or more races. 44.6% of the population are Hispanic or Latino of any race. The largest European-American ancestry groups are German (6%), Irish (5%), English (4%) and Italian (3%). 45.9% of the population reported speaking only English at home; 37.9% spoke Spanish, 2.22% Tagalog, 2.0% Chinese, 1.9% Korean, and 1.6% Armenian. [1]

Because the county is so populous, what is not so evident is that it has the largest Native American population of any county in the nation: according to the 2000 census, it has more than 153,550 people of indigenous descent, and most are from Latin America. "The invisible population that is virtually ignored by the census is that of indigenous people from Mexico, Central and South America."

There were 3,133,774 households out of which 36.80% had children under the age of 18 living with them, 47.6% were married couples living together, 14.7% had a female householder with no husband present, and 31.8% were non-families. 24.6% of all households were made up of individuals and 7.1% had someone living alone who was 65 years of age or older. The average household size was 2.98 and the average family size was 3.61.

In the county the population was spread out with 28.0% under the age of 18, 10.3% from 18 to 24, 32.6% from 25 to 44, 19.4% from 45 to 64, and 9.7% who were 65 years of age or older. The median age was 32 years. For every 100 females there were 97.7 males. For every 100 females age 18 and over, there were 95.0 males.

The median income for a household in the county was $42,189, and the median income for a family was $46,452. Males had a median income of $36,299 versus $30,981 for females. The per capita income for the county was $20,683. There are 14.4% of families living below the poverty line and 17.9% of the population, including 24.2% of under 18 and 10.5% of those over 64.

According to TNS Financial Services, Los Angeles County has the highest number of millionaires of any county in the nation, totaling 261,081 households as of 2007, with about 1 out of every 38 households worth more than $1 million (not including primary residence). In addition to millionaires, Los Angeles County has the largest number of homeless people, with "48,000 people living on the streets, including 6,000 veterans."

2008 Demographics

Housing

The homeownership rate is 47.9%, and the median value for houses is $409,300. 42.2% of housing units are in multi-unit structures.

Law, government and politics

The county's voters elect a governing five-member Los Angeles County Board of Supervisors. The small size of the board means each supervisor represents over 2 million people. The board operates in a legislative, executive, and quasi-judicial capacity. As a legislative authority, it can pass ordinances for the unincorporated areas (ordinances that affect the whole county, like posting of restaurant ratings, must be ratified by the individual city). As an executive body, it can tell the county departments what to do, and how to do it. As a quasi-judicial body, the Board is the final venue of appeal in the local planning process, and holds public hearings on various agenda items.

As of 2008, the Board of Supervisors oversees a $22.5 billion annual budget and approximately 100,000 employees. The county government is managed on a day-to-day basis by a Chief Executive Officer, currently William T Fujioka, and is organized into many departments, each of which is enormous in comparison to equivalent county-level (and even state-level) departments anywhere else in the United States. Some of the larger or better-known departments include:

The Los Angeles Superior Court, which covers the entire county, is not a County department but a division of the State's trial court system. Historically, the courthouses were county-owned buildings that were maintained at county expense, which created significant friction since the trial court judges, as officials of the state government, had to lobby the county Board of Supervisors for facility renovations and upgrades. In turn, the state judiciary successfully persuaded the state Legislature to authorize the transfer of all courthouses to the state government in 2008 and 2009 (so that judges would have direct control over their own courthouses). Courthouse security is still provided by the county government under a contract with the state.

Legal system

Unlike the largest city in the US, New York City, all of the city of Los Angeles and most of its important suburbs are located within a single county. As a result, both the county superior court and the federal district court are respectively the busiest courts of their type in the nation.

Many celebrities like O.J. Simpson have been seen in Los Angeles courts. In 2003, the tabloid television show Extra (based in nearby Glendale) found itself running so many reports on the legal problems of local celebrities that it spun them off into a separate show, Celebrity Justice.

State cases are appealed to the Court of Appeal for the Second Appellate District, which is also headquartered in the Civic Center, and then to the California Supreme Court, which is headquartered in San Francisco but also hears argument in Los Angeles (again, in the Civic Center). Federal cases are appealed to the Court of Appeals for the Ninth Circuit, which hears them at its branch building in Pasadena. The court of last resort for federal cases is the U.S. Supreme Court in Washington, D.C.

Education

Colleges and universities

Religion

As of 2000, there are hundreds of Christian churches, 202 Jewish synagogues, 145 Buddhist temples, 48 Islamic mosques, 44 Bahai worship centers, 37 Hindu temples, 28 Tenrikyo churches and fellowships, 16 Shinto worship centers, 14 Sikh gurdwaras in the county. The Los Angeles Archdiocese has approximately 5 million members and is the largest in the United States.

Sites of interest

Venice Beach is a popular attraction where its Muscle Beach used to find throngs of tourists admiring "hardbodies". Today it is more arts-centered. Santa Monica's pier is a well known tourist spot, famous for its ferris wheel and bumper car rides, which were featured in the introductory segment of the television sitcom Three's Company. Further north in Pacific Palisades one finds the beaches used in the television series Baywatch. The fabled Malibu, home of many a film or television star, lies west of it.

In the mountain, canyon, and desert areas one may find Vasquez Rocks Natural Area Park, where many old westerns were filmed. Mount Wilson Observatory in the San Gabriel Mountains is open for the public to view astronomical stars from its telescope, now computer-assisted. Many county residents find relaxation in water skiing and swimming at Castaic Lake Recreation Area – the county's largest park by area – as well as enjoying natural surroundings and starry nights at Saddleback Butte State Park in the eastern Antelope Valley – California State Parks' largest in area within the county. The California Poppy Reserve is located in the western Antelope Valley and shows off the State's flower in great quantity on its rolling hills every spring.

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