20200731 Dementia

Friday, 31 July

#Today I wanna write about a disease which contracted by my mom. It was Dementia.

https://images.app.goo.gl/LmuReTSLCjgR84xa8

Dementia is a broad category of brain disease that cause a long-term and often gradual decrease in the ability to think and remember that is severe enough to affect daily functioning. Other common symptoms include emotional problems, difficulties with language, and a decrease in motivation. Consciousness is usually not affected. A diagnosis of dementia requires a change from a person's usual mental functioning and a greater decline than one would expect due to aging. These diseases have a significant effect on caregivers. 

The most common type of dementia is Alzheimer's disease, which makes up 50% to 70% of cases. Other common types include vascular dementia (25%), dementia with Lewy bodies (15%), and frontotemporal dementia. Less common causes include normal pressure hydrocephalus, Parkinson's disease dementia, syphilis, HIV, and Creutzfeldt-Jakob disease. More than one type of dementia may exist in the same person. A small proportion of cases run in families. In the DSM-5, dementia was reclassified as a neurocognitive disorder, with degrees of severity. Diagnosis is usually based on history of the illness and cognitive testing with medical imaging and blood tests used to rule out other possible causes. The mini mental state examination is one commonly used cognitive test. Efforts to prevent dementia include trying to decrease risk factors such as high blood pressure, smoking, diabetes, and obesity. Screening the general population for the disorder is not recommended.

There is no known cure for dementia. Cholinesterase inhibitors such as donepezil are often used and may be beneficial in mild to moderate disorder. Overall benefit, however, may be minor. There are many measures that can improve the quality of life of people with dementia and their caregivers. Cognitive and behavioral interventions may be appropriate. Educating and providing emotional support to the caregiver is important. Exercise programs may be beneficial with respect to activities of daily living and potentially improve outcomes. Treatment of behavioral problems with antipsychotica is common but not usually recommended, due to the limited benefit and the side effects, including an increased risk of death.

Globally, dementia affected about 46 million people in 2015. About 10% of people develop the disorder at some point in their lives. It becomes more common with age. About 3% of people between the ages of 65–74 have dementia, 19% between 75 and 84, and nearly half of those over 85 years of age. In 2013 dementia resulted in about 1.7 million deaths, up from 0.8 million in 1990. As more people are living longer, dementia is becoming more common. For people of a specific age, however, it may be becoming less frequent, at least in the developed world, due to a decrease in risk factors. It is one of the most common causes of disability among the old. It is believed to result in economic costs of US$604 billion a year. People with dementia are often physically or chemically restrained to a greater degree than necessary, raising issues of human rights. Social stigma against those affected is common.

The symptoms of dementia vary across types and stages of the diagnosis. The most commonly affected areas include memory, visual-spatial perception and orientation, language, attention and problem solving. Most types of dementia are slow and progressive. By the time signs of the disorder are apparent, deterioration in the brain has been happening for a long time.

Neuropsychiatric symptoms that may be present are termed Behavioural and psychological symptoms of dementia (BPSD). These can include problems with:

• Balance
• Tremor
• Speech and language
• Eating/swallowing
• Memory (believing that a memory has already happened when it has not, thinking an old memory is a new one, combining two memories, or confusing the people in a memory)
• Wandering or restlessness
• Visual perception

Behavioral and psychological symptoms of dementia almost always occur in all types of dementia and may manifest as:

• Agitation
• Depression
• Anxiety
• Abnormal motor behavior
• Elated mood
• Irritability
• Apathy
• Disinhibition and impulsivity
• Delusions (often believing people are stealing from them) or hallucinations
• Changes in sleep or appetite.

When people with dementia are put in circumstances beyond their abilities, they may experience a sudden change to crying or anger (a "catastrophic reaction").

Psychosis (often delusions of persecution) and agitation/aggression also often accompany dementia. 

In the first stages of dementia, signs and symptoms may be subtle. Often, the early signs become apparent when looking back in time. The earliest stage of dementia is called Mild Cognitive Impairment (MCI). 70% of those diagnosed with MCI later progress to dementia. In MCI, changes in the person's brain have been happening for a long time, but symptoms are just beginning to appear. These problems, however, are not severe enough to affect daily function. If/once they do, the diagnosis becomes dementia. A person with MCI scores between 27 and 30 on the Mini-Mental State Examination (MMSE), which is a normal score. They may have some memory trouble and trouble finding words, but they solve everyday problems and competently handle their life affairs. 

In the early stage of dementia, symptoms become noticeable to others. In addition, the symptoms begin to interfere with daily activities. MMSE scores are between 20 and 25. The symptoms are dependent on the type of dementia. More complicated chores and tasks around the house or at work become more difficult. The person can usually still take care of themselves but may forget things like taking pills or doing laundry and may need prompting or reminders.

The symptoms of early dementia usually include memory difficulty, but can also include some word-finding problems (anomia) and problems with planning and organizational skills (executive function). One very good way of assessing a person's impairment is by asking if they are still able to handle their finances independently. This is often one of the first things to become problematic. Other signs might be getting lost in new places, repeating things, personality changes, social withdrawal and difficulties at work.

When evaluating dementia, it is important to consider how the person functioned five or ten years earlier. It is also important to consider education level when assessing function. For example, an accountant who can no longer balance a checkbook would be more concerning than a person who had not finished high school or had never taken care of their own finances.

In Alzheimer's dementia the most prominent early symptom is memory difficulty. Others include word-finding problems and getting lost. In other types of dementia, such as dementia with Lewy bodies and fronto-temporal dementia, personality changes and difficulty with organization and planning may be the first signs.

As dementia progresses, initial symptoms generally worsen. The rate of decline is different for each person. MMSE between scores of 6–17 signal moderate dementia . For example, people with moderate Alzheimer's dementia lose almost all new information. People with dementia may be severely impaired in solving problems, and their social judgment is usually also impaired. They cannot usually function outside their own home, and generally should not be left alone. They may be able to do simple chores around the house but not much else, and begin to require assistance for personal care and hygiene beyond simple reminders.

People with late-stage dementia typically turn increasingly inward and need assistance with most or all of their personal care. Persons with dementia in the late stages usually need 24-hour supervision to ensure personal safety, as well as to ensure meeting basic needs. If left unsupervised, a person with late-stage dementia may wander or fall, may not recognize common dangers such as a hot stove, or may not realize that they need to use the bathroom. They may become incontinent. 

Changes in eating frequently occur. People with late-stage dementia often eat pureed diets, thickened liquids, and require assistance in eating, to prolong their lives, to cause them to retain weight, to reduce choking risk and to make eating easier. The person's appetite may decline to the point that the person does not want to eat at all. They may not want to get out of bed, or may need assistance doing so. Commonly, the person no longer recognizes familiar faces. They may have significant changes in sleeping habits or have trouble sleeping at all.

Causes of easily reversible dementia include hypothyroidism, vitamin B12 deficiency, Lyme disease, and neurosyphilis. All people with memory difficulty should be checked for hypothyroidism and B12 deficiency. For Lyme disease and neurosyphilis, testing should be done if risk factors are present. Because risk factors are often difficult to determine, testing for neurosyphilis and Lyme disease, as well as other mentioned factors, may be undertaken as a matter of course where dementia is suspected. Hearing loss may also be associated with dementia. Hearing aids may have some benefit. 

Alzheimer's disease accounts for 50% to 70% of cases of dementia. The most common symptoms of Alzheimer's disease are short-term memory loss and word-finding difficulties. Trouble with visual-spatial processing (for example, they may begin to get lost often), reasoning, judgment and insight fail. Insight refers to whether or not the person realizes they have memory problems.

Common early symptoms of Alzheimer's include repetition, getting lost, difficulties tracking bills, problems with cooking especially new or complicated meals, forgetting to take medication and word-finding problems.

The part of the brain most affected by Alzheimer's is the hippocampus. Other parts that show atrophy (shrinking) include the temporal and parietal libes. Although this pattern suggests Alzheimer's, the brain shrinkage in Alzheimer's disease is variable, and a brain scan is not sufficient for diagnosis. The relationship between anesthesia and AD is unclear.

Vascular dementia accounts for at least 20% of dementia cases, making it the second most common type. It is caused by disease or injury affecting the blood supply to the brain, typically involving a series of mini-stroke. The symptoms of this dementia depend on where in the brain the strokes occurred and whether the vessels are large or small. Multiple injuries can cause progressive dementia over time, while a single injury located in an area critical for cognition such as the hippocampus, or thalamus, can lead to sudden cognitive decline.

Brain scans may show evidence of multiple strokes of different sizes in various locations. People with vascular dementia tend to have risk factors for disease of the blood vessels, such as tobacco use, high blood pressure, atrial fibrillation, high cholesterol or diabetes, or other signs of vascular disease such as a previous heart attack or angina.

Dementia with Lewy Bodies (DLB) has the primary symptoms of visual hallucinations and "Parkinsonism". Parkinsonism is the symptoms of Parkinson's disease, which include tremor, rigid muscles, and a face without emotion. The visual hallucinations in DLB are generally vivid hallucinations of people or animals and they often occur when someone is about to fall asleep or wake up. Other prominent symptoms include problems with attention, organization, problem solving and planning (executive function) and difficulty with visual-spatial function.

Again, imaging studies cannot determine the diagnosis of DLB, but some changes are particularly common. A person with DLB often shows occipital hypoperfusion on a SPECT scan or occipital hypometabolism on a PET scan. Generally, a diagnosis of DLB is straightforward and typically does not require a brain scan.

Frontotemporal dementias (FTDs) are characterized by drastic personality changes and language difficulties. In all FTDs, the person has a relatively early social withdrawal and early lack of insight. Memory problems are not a main feature.

There are six main types of FTD. The first has major symptoms in personality and behavior. This is called behavioral variant FTD (bv-FTD) and is the most common. In bv-FTD, the person shows a change in personal hygiene, becomes rigid in their thinking, and rarely acknowledges problems; they are socially withdrawn, and often have a drastic increase in appetite. They may become socially inappropriate. For example, they may make inappropriate sexual comments, or may begin using pornography openly. One of the most common signs is apathy, or not caring about anything. Apathy, however, is a common symptom in many dementias

Two types of FTD feature aphasia (language problems) as the main symptom. One type is called semantic variant primary progressive aphasia (SV-PPA). The main feature of this is the loss of the meaning of words. It may begin with difficulty naming things. The person eventually may lose the meaning of objects as well. For example, a drawing of a bird, dog, and an airplane in someone with FTD may all appear almost the same. In a classic test for this, a patient is shown a picture of a pyramid and below it a picture of both a palm tree and a pine tree. The person is asked to say which one goes best with the pyramid. In SV-PPA the person cannot answer that question. The other type is called non-fluent agrammatic variant primary progressive aphasia (NFA-PPA). This is mainly a problem with producing speech. They have trouble finding the right words, but mostly they have a difficulty coordinating the muscles they need to speak. Eventually, someone with NFA-PPA only uses one-syllable words or may become totally mute.

Progressive Supranuclear Palsy (PSP) is a form of FTD that is characterized by problems with eye movements. Generally the problems begin with difficulty moving the eyes up or down (vertical gaze palsy). Since difficulty moving the eyes upward can sometimes happen in normal aging, problems with downward eye movements are the key in PSP. Other key symptoms include falling backward, balance problems, slow movements, rigid muscles, irritability, apathy, social withdrawal and depression. The person may have certain "frontal lobe" signs such as perseveration, a grasp reflex and utilization behavior (the need to use an object once you see it). People with PSP often have progressive difficulty eating and swallowing, and eventually with talking. Because of the rigidity and slow movements, PSP is sometimes misdiagnosed as Parkinson's disease. On scans the midbrain of people with PSP is generally shrunken (atrophied), but no other common brain abnormalities are visible.

Corticobasal degeneration (CBD) is a rare form of FTD that is characterized by many different types of neurological problems that progressively worsen. This is because the disorder affects the brain in many different places, but at different rates. One common sign is difficulty with using only one limb. One symptom that is rare in any other condition is the "alien limb". The alien limb is a limb that seems to have a mind of its own, it moves without conscious control of the person's brain. Other common symptoms include jerky movements of one or more limbs (myoclonus), symptoms that are different in different limbs (asymmetric), difficulty with speech from inability to move the mouth muscles in a coordinated way, numbness and tingling of the limbs and neglecting one side of vision or senses. In neglect, a person ignores the opposite side of the body from the one that has the problem. For example, a person may not feel pain on one side, or may only draw half of a picture when asked. In addition, the person's affected limbs may be rigid or have muscle contractions causing dystonia (strange repetitive movements). The brain area most often affected in corticobasal degeneration is the posterior frontal lobe and parietal lobe, although many other parts can be affected.

Finally, FT dementia associated with MND (FTD-MND) includes the symptoms of FTD (behavior, language and movement problems) co-occurring with amyotrophic lateral sclerosis (death of motor neurons).

Creutzfeldt-Jakob disease typically causes a dementia that worsens over weeks to months, and is 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.

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; chronic subdural hematoma; and repeated brain trauma (chronic traumatic encephalopathy, a condition associated with contact sports). 

Chronic inflammatory conditions that may affect the brain and cognition include Behçet's disease, multiple sclerosis, sarcoidosis, Sjögren's syndrome, systemic lupus erythematosus, celiac disease, and non-celiac gluten sensitivity. These types of dementias can rapidly progress, but usually have a good response to early treatment. This consists of immunomodulators or steroid administration, or in certain cases, the elimination of the causative agent.^[44] A 2019 review found no association between celiac disease and dementia overall but a potential association with vascular dementia. A 2018 review found a link between celiac disease or non-celiac gluten sensitivity and cognitive impairment and that celiac disease may be associated with Alzheimer's disease, vascular dementia, and frontotemporal dementia. A strict gluten-free diet started early may protect against dementia associated with gluten-related disorders. 

Many other medical and neurological conditions include dementia only late in the illness. 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). Although the acute porphyrias may cause episodes of confusion and psychiatric disturbance, dementia is a rare feature of these rare diseases. Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a type of dementia that primarily affects people in their 80s or 90s and in which TDP-43 protein deposits in the limbic portion of the brain.

Aside from those mentioned above, heritable conditions that can cause dementia (alongside other symptoms) include:

• Alexander disease
• Canavan disease
• Cerebrotendinous xanthomatois
• Dentatorubral-pallidoluysian atrophy
• Epilepsy
• Fatal familial insomnia
• Fragile X-associated tremor / ataxia syndrome
• Glutaric aciduria type 1
• Krabbe's disease
• Maple syrup urine disease
• Niemann-Pick disease type C
• Neuronal ceroid lipofuscinosis
• Neuroacanthocytosis
• Organic acidemias
• Pelizaeus-Merzbacher disease
• Sanfilippo syndrome type B
• Spinocerebellar ataxia type 2
• Urea cycle disorders

Mild cognitive impairment means that the person exhibits memory or thinking difficulties, but those difficulties are not severe enough for a diagnosis of dementia. They should score between 25–30 on the MMSE. Around 70% of people with MCI go on to develop some form of dementia. MCI is generally divided into two categories. The first is primarily memory loss (amnestic MCI). The second is anything else (non-amnestic MCI). People with primarily memory problems typically develop Alzheimer's disease. People with the other type of MCI may develop other types of dementia.

Diagnosis of MCI is often difficult, as cognitive testing may be normal. Often, more in-depth neuropsychological testing is necessary to make the diagnosis. The most commonly used criteria are called the Peterson criteria and include:

• Memory or other cognitive (thought-processing) complaint by the person or a person who knows the patient well.
• A memory or other cognitive problem as compared to a person of the same age and level of education.
• Symptoms not severe enough to affect daily function.
• Absence of dementia. 

Various types of brain injury may cause irreversible cognitive impairment that remains stable over time. Traumatic brain injury may cause generalized damage to the white matter of the brain (diffuse axonal injury), or more localized damage (as may also accompany neurosurgery). A temporary reduction in the brain's blood supply or oxygen may lead to hypoxic-ischemic injury. Strokes (ischemic stroke, or intracerebral, subarachnoid, subdural or extradural hemorrhage) or infections (meningitis 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, or Korsakoff's psychosis.

Dementia that begins gradually and worsens over several years is usually caused by neurodegenerative disease - that is, by conditions that affect only or primarily brain neurons and cause gradual but irreversible loss of function. 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.

Causes of dementia depend on the age when symptoms begin. In the elderly population, a large majority of dementia cases are caused by Alzheimer's disease, vascular dementia, or dementia with Lewy bodies. Hypothyroidism sometimes causes slowly progressive cognitive impairment as the main symptom, which 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 disorder 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 football players, are at risk of chronic traumatic encephalopathy. (also called dementia pugilistica in boxers).

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 have 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, AIDS, Lyme disease, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, syphilis, and Whipple's disease. 

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a type of dementia similar to Alzheimer disease which was proposed in 2019. Usually older people are affected.

Hearing loss is linked with dementia with a greater degree of hearing loss tied to a higher risk. One hypothesis is that as hearing loss increases, cognitive resources are redistributed to auditory perception to the detriment of other cognitive processes. Another hypothesis is that hearing loss leads to social isolation which negatively affect the cognitive functions.

About 10% of people with dementia have what is known as mixed dementia, which is usually a combination of Alzheimer's disease and another type of dementia such as frontotemporal dementia or vascular dementia. 

Symptoms are similar across dementia types and it is difficult to diagnose by symptoms alone. Diagnosis may be aided by brain scanning techniques. In many cases, the diagnosis requires a brain biopsy to become final, but this is rarely recommended (though it can be performed at autopsy). In those who are getting older, general screening for cognitive impairment using cognitive testing or early diagnosis of dementia has not been shown to improve outcomes. However, screening exams are useful in 65+ persons with memory complaints.

Normally, symptoms must be present for at least six months to support a diagnosis. Cognitive dysfunction of shorter duration is called delirium. Delirium can be easily confused with dementia due to similar symptoms. Delirium is characterized by a sudden onset, fluctuating course, a short duration (often lasting from hours to weeks), and is primarily related to a somatic (or medical) disturbance. In comparison, dementia has typically a long, slow onset (except in the cases of a stroke or trauma), slow decline of mental functioning, as well as a longer trajectory (from months to years).

Some mental illness, including depression and psychosis, may produce symptoms that must be differentiated from both delirium and dementia. Therefore, any dementia evaluation should include a depression screening such as the Neuropsychiatric Inventory or the Geriatric Depression Scale. Physicians used to think that people with memory complaints had depression and not dementia (because they thought that those with dementia are generally unaware of their memory problems). This is called pseudodementia. However, in recent years researchers have realized that many older people with memory complaints in fact have MCI, the earliest stage of dementia. Depression should always remain high on the list of possibilities, however, for an elderly person with memory trouble.

Changes in thinking, hearing and vision are associated with normal ageing and can cause problems when diagnosing dementia due to the similarities.

Various brief tests (5–15 minutes) have reasonable reliability to screen for dementia. While many tests have been studied, presently the Mini Mental State Examination (MMSE) is the best studied and most commonly used. The MMSE is a useful tool for helping to diagnose dementia if the results are interpreted along with an assessment of a person's personality, their ability to perform activities of daily living, and their behaviour. Other cognitive tests include the Abbreviated Mental Test Score (AMTS), the, Modified Mini-Mental State Examination (3MS), the Cognitive Abilities Screening Instrument (CASI), the Trail-making test, and the clock drawing test. The MoCA (Montreal Cognitive Assessment) is a reliable screening test and is available online for free in 35 different languages. The MoCA has also been shown somewhat better at detecting mild cognitive impairment than the MMSE. The AD-8 – a screening questionnaire used to assess changes in function related to cognitive decline – is potentially useful, but is not diagnostic, is variable, and has risk of bias. Brief cognitive tests may be affected by factors such as age, education and ethnicity.

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). Evidence is insufficient to determine how accurate the IQCODE is for diagnosing or predicting dementia. The Alzheimer's Disease Caregiver Questionnaire is another tool. It is about 90% accurate for Alzheimer's when by a caregiver. The General Practitioner Assessment Of Cognition combines both a patient assessment and an informant interview. It was specifically designed for use in the primary care setting.

Clinical neuropsychologists provide diagnostic consultation following administration of a full battery of cognitive testing, often lasting several hours, to determine functional patterns of decline associated with varying types of dementia. Tests of memory, executive function, processing speed, attention and language skills are relevant, as well as tests of emotional and psychological adjustment. These tests assist with ruling out other etiologies and determining relative cognitive decline over time or from estimates of prior cognitive abilities.

Instead of using “mild or early stage”, “middle stage”, and “late stage” dementia as descriptors, numeric scales allow more detailed descriptions. These scales include: Global Deterioration Scale for Assessment of Primary Degenerative Dementia (GDS or Reisberg Scale), Functional Assessment Staging Test (FAST), and Clinical Dementia Rating (CDR).

Routine blood tests are 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. 

A CT scan or Magnetic Resonance Imaging (MRI scan) is commonly performed, although these tests do not pick up diffuse metabolic changes associated with dementia in a person who shows no gross neurological problems (such as paralysis or weakness) on a 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 and cognitive testing. The ability of SPECT to differentiate the vascular cause (i.e., multi-infarct dementia) from Alzheimer's disease dementias, appears 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, particularly Alzheimer's disease. Studies reported that PIB-PET was 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, 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.

Various factors can decrease the risk of dementia. As a group they may be able to prevent a third of cases. The group includes early education, treating high blood pressure, preventing obesity, preventing hearing loss, treating depression, physical activity, preventing diabetes, not smoking, and social connection. The decreased risk with a healthy lifestyle is seen even in those with a high genetic risk. A 2018 review however concluded that no medications have good evidence of a preventive effect, including blood pressure medications. A 2020 review found a decrease in the risk of dementia or cognitive problems from 7.5% to 7.0% with blood pressure lowering medications.

Among otherwise healthy older people, computerized cognitive training may, in the short term, improve memory. However it is not known whether it prevents dementia. Exercise has poor evidence of preventing dementia. In those with normal mental function evidence for medications is poor. The same applies to supplements. 

The early introduction of a strict gluten-free diet in people with celiac disease or non-celiac gluten sensitivity before cognitive impairment begins potentially has a protective effect.

Until the end of the 19th century, dementia was a much broader clinical concept. It included mental illness and any type of psychosocial incapacity, including reversible conditions. Dementia at this time simply referred to anyone who had lost the ability to reason, and was applied equally to psychosis, "organic" diseases like syphilis that destroy the brain, and to the dementia associated with old age, which was attributed to "hardening of the arteries".

Dementia has been referred to in medical texts since antiquity. One of the earliest known allusions to dementia is attributed to the 7th-century BC Greek philosopher Pythagoras, who divided the human lifespan into six distinct phases: 0–6 (infancy), 7–21 (adolescence), 22–49 (young adulthood), 50–62 (middle age), 63–79 (old age), and 80–death (advanced age). The last two he described as the "senium", a period of mental and physical decay, and that the final phase was when "the scene of mortal existence closes after a great length of time that very fortunately, few of the human species arrive at, where the mind is reduced to the imbecility of the first epoch of infancy". In 550 BC, the Athenian statesman and poet Solon argued that the terms of a man's will might be invalidated if he exhibited loss of judgement due to advanced age. Chinese medical texts made allusions to the condition as well, and the characters for "dementia" translate literally to "foolish old person".

Athenians Aristotle and Plato spoke of the mental decay of advanced age, apparently viewing it as an inevitable process that affected all old men, and which nothing could prevent. Plato stated that the elderly were unsuited for any position of responsibility because, "There is not much acumen of the mind that once carried them in their youth, those characteristics one would call judgement, imagination, power of reasoning, and memory. They see them gradually blunted by deterioration and can hardly fulfill their function."

For comparison, the Roman statesman Cicero held a view much more in line with modern-day medical wisdom that loss of mental function was not inevitable in the elderly and "affected only those old men who were weak-willed". He spoke of how those who remained mentally active and eager to learn new things could stave off dementia. However, Cicero's views on aging, although progressive, were largely ignored in a world that would be dominated for centuries by Aristotle's medical writings. Physicians during the Roman Empire, such as Galen and Celsus, simply repeated the beliefs of Aristotle while adding few new contributions to medical knowledge.

Byzantine physicians sometimes wrote of dementia. It is recorded that at least seven emperors whose lifespans exceeded 70 years displayed signs of cognitive decline. In Constantinople, special hospitals housed those diagnosed with dementia or insanity, but these did not apply to the emperors, who were above the law and whose health conditions could not be publicly acknowledged.

Otherwise, little is recorded about dementia in Western medical texts for nearly 1700 years. One of the few references was the 13th-century friar Roger Bacon, who viewed old age as divine punishment for original sin. Although he repeated existing Aristotelian beliefs that dementia was inevitable, he did make the progressive assertion that the brain was the center of memory and thought rather than the heart.

Poets, playwrights, and other writers made frequent allusions to the loss of mental function in old age. William shakespeare notably mentions it in plays such as Hamlet and King Lear. 

During the 19th century, doctors generally came to believe that elderly dementia was the result of cerebral atherosclerosis, although opinions fluctuated between the idea that it was due to blockage of the major arteries supplying the brain or small strokes within the vessels of the cerebral cortex. 

In 1907 Alzheimer's disease was described. This was associated with particular microscopic changes in the brain, but was seen as a rare disease of middle age because the first person diagnosed with it was  a 50 year old woman. By 1913–20, schizophrenia had been well-defined in a way similar to later times.

This viewpoint remained conventional medical wisdom through the first half of the 20th century, but by the 1960s it was increasingly challenged as the link between neurodegenerative diseases and age-related cognitive decline was established. By the 1970s, the medical community maintained that vascular dementia was rarer than previously thought and Alzheimer's disease caused the vast majority of old age mental impairments. More recently however, it is believed that dementia is often a mixture of conditions.

In 1976, neurologist Robert Katzmann suggested a link between senile dementia and Alzheimer's disease. Katzmann suggested that much of the senile dementia occurring (by definition) after the age of 65, was pathologically identical with Alzheimer's disease occurring in people under age 65 and therefore should not be treated differently. Katzmann thus suggested that Alzheimer's disease, if taken to occur over age 65, is actually common, not rare, and was the fourth- or 5th-leading cause of death, even though rarely reported on death certificates in 1976.

A helpful finding was that although the incidence of Alzheimer's disease increased with age (from 5–10% of 75-year-olds to as many as 40–50% of 90-year-olds), no threshold was found by which age all persons developed it. This is shown by documented supercentenarians (people living to 110 or more) who experienced no substantial cognitive impairment. Some evidence suggests that dementia is most likely to develop between ages 80 and 84 and individuals who pass that point without being affected have a lower chance of developing it. Women account for a larger percentage of dementia cases than men, although this can be attributed to their longer overall lifespan and greater odds of attaining an age where the condition is likely to occur.

Much like other diseases associated with aging, dementia was comparatively rare before the 20th century, because few people lived past 80. Conversely, syphilitic dementia was widespread in the developed world until it was largely eradicated by the use of penicillin after World War II. With significant increases in life expectancy thereafter, the number of people over 65 started rapidly climbing. While elderly persons constituted an average of 3–5% of the population prior to 1945, by 2010 many countries reached 10–14% and in Germany and Japan, this figure exceeded 20%. Public awareness of Alzheimer's Disease greatly increased in 1994 when former US president Ronald Reagan announced that he had been diagnosed with the condition.

In the 21st century, other types of dementia were differentiated from Alzheimer's disease and vascular dementias (the most common types). This differentiation is on the basis of pathological examination of brain tissues, by symptomatology, and by different patterns of brain metabolic activity in nuclear medical imaging tests such as SPECT and PET scans of the brain. The various forms have differing prognoses and differing epidemiologic risk factors. The causal etiology of many of them, including Alzheimer's disease, remains unclear.

Dementia in the elderly was once called senile dementia or senility, and viewed as a normal and somewhat inevitable aspect of growing old. This terminology is no longer standard.

By 1913–20 the term dementia praecox was introduced to suggest the development of senile-type dementia at a younger age. Eventually the two terms fused, so that until 1952 physicians used the terms dementia praecox (precocious dementia) and schizophrenia interchangeably. The term precocious dementia for a mental illness suggested that a type of mental illness like schizophrenia (including paranoia and decreased cognitive capacity) could be expected to arrive normally in all persons with greater age (see paraphrenia). After about 1920, the beginning use of dementia for what is now understood as schizophrenia and senile dementia helped limit the word's meaning to "permanent, irreversible mental deterioration". This began the change to the later use of the term.

The view that dementia must always be the result of a particular disease process led for a time to the proposed diagnosis of "senile dementia of the Alzheimer's type" (SDAT) in persons over the age of 65, with "Alzheimer's disease" diagnosed in persons younger than 65 who had the same pathology. Eventually, however, it was agreed that the age limit was artificial, and that Alzheimer's disease was the appropriate term for persons with that particular brain pathology, regardless of age.

After 1952, mental illnesses including schizophrenia were removed from the category of organic brain syndromes, and thus (by definition) removed from possible causes of "dementing illnesses" (dementias). At the same, however, the traditional cause of senile dementia – "hardening of the arteries" – now returned as a set of dementias of vascular cause (small strokes). These were now termed multi-infarct dementias or  vascular dementias.

(https://en.m.wikipedia.org/wiki/Dementia)

#enoughfortoday #qmo

20200730 Alzheimer's disease

Thursday, 30 July

#Today I wanna write about Alzheimer's disease. 

https://images.app.goo.gl/9G3v2Mc8fHwBbbQQ9

Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a chronic neurodegenerative disease that usually starts slowly and gradually worsens over time. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering eecent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self-care, and behavioural issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.

The cause of Alzheimer's disease is poorly understood. About 70% of the risk is believed to be inherited from a person's parents, with many genes usually involved. Other risk factors include a history of head injuries, depression, and hypertension. The disease process is associated with plaques and neurofibrillary tangles in the brain. A probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood test to rule out other possible causes. Initial symptoms are often mistaken for normal ageing. Examination of brain tissue is needed for a definite diagnosis. Mental and physical exercise, and avoiding obesity may decrease the risk of AD; however, evidence to support these recommendations is weak. There are no medications or supplements that have been shown to decrease risk.

No treatments stop or reverse its progression, though some may temporarily improve symptoms. Affected people increasingly rely on others for assistance, often placing a burden on the caregiver. The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioural problems or psychosis due to dementia are often treated with antipsychosis, but this is not usually recommended, as there is little benefit and an increased risk of early death.

In 2015, there were approximately 29.8 million people worldwide with AD. It most often begins in people over 65 years of age, although 4–5% of cases are early-onset Alzheimer's. It affects about 6% of people 65 years and older. In 2015, dementia resulted in about 1.9 million deaths. It was first described by, and later named after, German psychiatrist and pathologist Alois Alzheimer in 1906. In developed countries, AD is one of the most financially costly diseases.

Signs and symptoms

Stages of Alzheimer's disease

Effect of ageing on memory but not AD

• Forgetting things occasionally
• Misplacing items sometimes
• Minor short-term memory loss
• Not remembering exact details

Early stage Alzheimer's

• Not remembering episodes of forgetfulness
• Forgets names of family or friends
• Changes may only be noticed by close friends or relatives
• Some confusion in situations outside the familiar

Middle stage Alzheimer's

• Greater difficulty remembering recently learned information
• Deepening confusion in many circumstances
• Problems with sleep
• Trouble determining their location

Late stage Alzheimer's

• Poor ability to think
• Problems speaking
• Repeats same conversations
• More abusive, anxious, or paranoid

The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment.  

The first symptoms are often mistakenly attributed to ageing 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 activities of daily living. The most noticeable deficit is short term 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. Depressive symptoms, irritability and reduced awareness of subtle memory difficulties are also common.  The preclinical stage of the disease has also been termed Mild Cognitive Impairment (MCI). This is often found to be a transitional stage between normal ageing and dementia. MCI can present with a variety of symptoms, and when memory loss is the predominant symptom, it is termed "amnestic MCI" and is frequently seen as a prodromal stage of Alzheimer's disease. 

In people with AD, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, 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 or how to drink from a glass) are affected to a lesser degree than new facts or memories.

Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately. 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.

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 people with AD develop illusionary misidentifications and other delysional symptoms. Subjects also lose insight of their disease process and limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and carers, which can be reduced by moving the person from home care to other ling-term care facilities.

During the final stages, 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, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself. 

The cause for most Alzheimer's cases is still mostly unknown except for 1% to 5% of cases where genetic differences have been identified. Several competing hypotheses exist trying to explain the cause of the disease. 

The genetic heritability of Alzheimer's disease (and memory components thereof), based on reviews of twin and family studies, ranges from 49% to 79%. Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset before age 65. This form of the disease is known as early onset familial Alzheimer's disease. Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding 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 Aβ42, which is the main component of senile plaques. Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels. Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1. 

Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD, in which environmental and genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). Between 40 and 80% of people with AD possess at least one APOEε4 allele. The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, certain Nigerian populations do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations. Early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield. More recent Genome-Wide Association Studies (GWAS) have found 19 areas in genes that appear to affect the risk. These genes include: CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SLC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, qnd CD2AP. 

Alleles in the TREM2 gene have been associated with a 3 to 5 times higher risk of developing Alzheimer's disease. A suggested mechanism of action is that in some variants in TREM2, white blood cells in the brain are no longer able to control the amount of beta amyloid present. Many Single-Nucleotide Polymorphisms (SNPs) are associated with Alzheimer's, with a 2018 study adding 30 SNPs by differentiating AD into 6 categories, including memory, language, visuospatial, and executive functioning.

The oldest hypothesis, 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.

In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (A_β) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the Amyloid 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 at least the earliest symptoms of AD by 40 years of age. Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain. 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_β oligomers (aggregates of many monomers) as the primary pathogenic form of A_β. 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_β 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 hypothesis 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 hypothesis 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 ageing-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 ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function. 

A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP. This mutation and its association with Alzheimer's disease was first reported in 2008. This mutation is known as the Osaka mutation. Only homozygotes with this mutation develop Alzheimer's disease. This mutation accelerates Aβ oligomerization but the proteins do not form amyloid fibrils suggesting that it is the Aβ oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all usual pathologies of Alzheimer's disease. 

The tau hypothesis proposes 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, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.

An inflammatory hypothesis is that AD is caused due to a self-perpetuating progressive inflammation in the brain culminating in neurodegeneration. A possible role of chronic periodontal infection and the gut microbiota has been suggested.

A neurovascular hypothesis has been proposed which states that poor functioning of the blood-brain barrier may be involved. Spirochete infections have also been linked to dementia.

The cellular homeostasis of biometals such as ionic copper, iron, and zinc is disrupted in AD, though it remains unclear whether this is produced by or causes the changes in proteins. These ions affect and are affected by tau, APP, and APOE, and their dysregulation may cause oxidative stress that may contribute to the pathology. The quality of some of these studies has been criticised, and the link remains controversial. The majority of researchers do not support a causal connection with aluminium.

Smoking is a significant AD risk factor. Systemic markers of the innate immune system are risk factors for late-onset AD.

There is tentative evidence that exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.

One hypothesis posits that dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which then causes amyloid production and tau hyper-phosphorylation as a side effect.

Retrogenesis is a medical hypothesis about the development and progress of Alzheimer's disease proposed by Barry Reisberg in the 1980s. The hypothesis is that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with AD go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter. Likewise the hypothesis is, that as infants go through states of cignitive development, people with AD go through the reverse process of progressive cognitive impairment. Reisberg developed the caregiving assessment tool known as "FAST" (Functional Assessment Staging Tool) which he says allows those caring for people with AD to identify the stages of disease progression and that provides advice about the kind of care needed at each stage.

The association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with CD, while a 2018 review found an association with several types of dementia including AD.

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. Degeneration is also present in brainstem nuclei like the locus coeruleus. Studies using MRI and PET have documented reductions in the size of specific brain regions in people with AD 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 insolube deposits of beta-amyloid 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 ageing, the brains of people with AD have a greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in the brains of people with AD.

Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by  plaque accumulation of abnormally folded amyloid beta protein and tau protein in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (A_β). A_β is a fragment from the larger Amyloid Precursor Protein (APP). APP is 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, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as senile plaques. 

AD is also considered a taupathy 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 stabilises 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. Pathogenic tau can also cause neuronal death through transposable element dysregulation.

Exactly how disturbances of production and aggregation of the beta-amyloid peptide give 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_β 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. There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.

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.

Alzheimer's disease is usually diagnosed based on the person's medical history, history from relatives, and behavioural observations. The presence of characteristic neurological and neuropsychological features and the absence of alternative conditions is supportive. Advanced Medical Imanging 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 practising physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically. 

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 intellectual domains are most commonly impaired in AD— memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive 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. 

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.

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 syphilis, rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals (e.g., lead, mercury) and anaemia. (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.

Due to low accuracy, the C-PIB-PET scan is not recommended to be used as an early diagnostic tool or for predicting the development of Alzheimer's disease when people show signs of mild cognitive impairment (MCI). The use of ¹⁸F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is also not supported by evidence.

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. 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.

Cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and worsened course of AD. Blood pressure medications may decrease the risk. Statins, which lower cholesterol however, have not been effective in preventing or improving the course of the disease.

Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) were thought in 2007 to be associated with a reduced likelihood of developing AD. Evidence also suggested the notion that NSAIDs could reduce inflammation related to amyloid plaques, but trials were suspended due to high adverse events. No prevention trial has been completed. They do not appear to be useful as a treatment, but as of 2011 were thought to be candidates as presymptomatic preventives. Hormone replacement therapy in menopause, although previously used, may increase the risk of dementia.

People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction how a reduced risk for Alzheimer's disease. This is compatible with the  cignitive 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 without changing the duration of the disease. Learning a second language even later in life seems to delay the onset of Alzheimer's disease.  Physical activity is also associated with a reduced risk of AD. Physical exercise is associated with decreased rate of dementia. Physical exercise is also effective in reducing symptom severity in those with Alzheimer's disease.

People who maintain a healthy, Japanese, or Mediterranean diet have a reduced risk of AD. A Mediterranean diet may improve outcomes in those with the disease. Those who eat a diet high in saturated fats and simple carbohydrates (mono and disaccharide) have a higher risk. The Mediterranean diet's beneficial cardiovascular effect has been proposed as the mechanism of action.

Conclusions on dietary components have at times been difficult to ascertain as results have differed between population-based studies and randomised controlled trials. There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD. There is tentative evidence that caffeine may be protective. A number of foods high in flavonoids such as cocoa, red wine, and tea may decrease the risk of AD.

Reviews on the use of vitamins and minerals have not found enough consistent evidence to recommend them. This includes vitamin A, C, the alpha-tocopherol form of vitamin E, selenium, zinc, and folic acid with or without vitamin B₁₂. Evidence from one randomized controlled trial indicated that the alpha-tocopherol form of vitamin E may slow cognitive decline, this evidence was judged to be "moderate" in quality. Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline. Omega-3 fatty acid supplements from plants and fish, and dietary docosahexaenoic acid (DHA), do not appear to benefit people with mild to moderate Alzheimer's disease.

Curcumin as of 2010 had not shown benefit in people even though there is tentative evidence in animals. There was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia. As of 2008 there was no concrete evidence that cannabinoids are effective in improving the symptoms of AD or dementia; however, some research into endocannabinoids looked promising.

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. 

Five medications are currently used to treat the cognitive problems of AD: four are acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil) and the other (memantine) is an NMDA receptors antagonist. The benefit from their use is small. No medication has been clearly shown to delay or halt 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. 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. 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, are mild to moderate in severity, and can be managed by slowly adjusting medication doses. Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased  gastric acid production. 

Glutamate is an 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 is a noncompetitive NMDA receptors 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 have a small benefit in the treatment of moderate to severe Alzheimer's disease. 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".

A typical antipsychotics are modestly useful in reducing aggression and psychosis in people with Alzheimer's disease, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline. When used in the long-term, they have been shown to associate with increased mortality. Stopping antipsychotic use in this group of people appears to be safe. 

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. Music therapy is effective in reducing behavioural and psychological symptoms.

Emotion-oriented interventions  include reminiscene therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. A Cochrane review has found no evidence that this is effective. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired people 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. A 2018 review of the effectiveness of RT found that effects were inconsistent, small in size and of doubtful clinical significance, and varied by setting. 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 no 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 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.

Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving is essentially 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. If eating becomes problematic, food will need to be prepared in smaller pieces or even 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, often with the help of hospice. 

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, named after him, in a fifty-year-old woman he called Auguste D. He followed her case until she died in 1906, when he first reported publicly on it. 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 on 15 July, 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 independent 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 to describe those who were 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. 

(https://en.m.wikipedia.org/wiki/Alzheimer%27s_disease)

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