Overview
Alzheimer’s disease (AD), also called Alzheimer disease, Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer’s, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and europathologist Alois Alzheimer in 1906 and was named after him. Generally, 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. 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 recognized symptom is memory loss, such as difficulty in remembering recently learned facts.
When a doctor or physician has been notified, and AD is suspected, the diagnosis is usually confirmed with behavioral assessments and cognitive tests, often followed by a brain scan if available. Comparison of a normal aged brain (left) and an Alzheimer’s patient’s brain (right). Differential characteristics are pointed out 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 yet available. As of 2008, more than 500 clinical trails 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.
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 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 the year 2000 both overall and in the 65 74 age group, with the rate increasing to 19% in the 75 84 groups and to 42% in the greater than 84 group. Prevalence rates in less developed regions are lower.
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 the year 2050. 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 non-medical 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 care-giving time and caregiver’s lost earnings, are taken into account. Costs increase with dementia severity and the presence of behavioral disturbances, and are related to the increased care-giving time required for the provision of physical care. Therefore any treatment that slows cognitive decline, delays institutionalization or reduces caregivers’ hours will have economic benefits. Economic evaluations of current treatments have shown positive results. eveloped 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 dementia 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 characterized 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 dementia 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 recognize close relatives. Long-term memory, which was previously intact, becomes impaired. Behavioral and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to care-giving. 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 dementia 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 by the disease itself.
Causes Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau protein Three major competing hypotheses exist 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 e 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. Oxidative stress is a significant cause in the formation of the pathology. AD individuals show 70% loss of locus ceruleus cells that provide norepinephrine (in addition to its neurotransmitter role ) that locally defuses from "varicosities" as an endogenous antiinflammato e onset. Silver impregnation. Neuropathology Alzheimer’s disease is characterized 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 abno 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 th so inhibits certain enzyme functions and the utilization 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 Alzh, , eimer’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 n 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 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. Assessment of intellectual functioning including memory testing can further characterize the state of the disease. Medical organizations have created diagnostic criteria to ease and standardize 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. PET scan of the brain of a person with AD showing a loss of function in the temporal lobe Diagnostic 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. Diagnostic tools Neuropsychological screening tests can help in the diagnosis of AD. In them, patients have to copy drawings similar to the one shown in the picture, remember words, read or sum. Neuropsychological 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 utilized in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease, over time, of the 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. 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. When available as a diagnostic tool, SPECT and 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.
Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins. Both 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. 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. Volumetric MRI, which can detect changes in the size of brain regions that atrophy during the progress of Alzheimer’s disease, is also showing promise as a diagnostic method. It may prove less expensive than other imaging methods currently under study. Recent studies suggest that brain metabolite levels may be utilized as biomarkers for Alzheimer’s disease. Prevention 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. 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. 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 criticized, and other studies have concluded that there is no relationship between these environmental factors and the development of AD. Electromagnetic fields (EMF) have also been proposed to be related to AD by some experts, but not others. Regarding extremely low frequency EMFs, while a meta-analysis found that exposed people had more than two-fold probabilities of having the disease, reviews do not agree on whether studies point towards a relationship, or not. Doubts on how to interpret the statistically significant results of the meta-analysis have been raised. Smoking is a significant AD risk factor. Systemic markers of the innate immune system are risk factors for late-onset AD.
Conventional Treatment
Currently there is no effective treatment for Alzheimer’s disease. The treatments are mainly to minimize various symptoms including psychiatric symptoms during the disease arising. The antipsychotic drugs can be administered when the patients show excited agitation and aggression. Antidepressants can be used for depressed patients. If the conditions cannot be controlled by drugs or patients are at risk of suicide, ECT can be carried out with caution. The main drugs currently used for treatment of Alzheimer’s disease include Corticorelin hydrochloride (Aricept) from Pfizer and Namenda from Forest Lab. They can treat some symptoms of Alzheimer’s disease but cannot prevent the progressive deterioration of the disease.
Limitations of Conventional Treatment
The main drugs currently used for treatment of Alzheimer’s disease include Corticorelin hydrochloride (Aricept) from Pfizer and Namenda from Forest Lab. They can treat some symptoms of Alzheimer’s disease but cannot prevent the progressive deterioration of the disease.
Stem Cell Treatment
Transplanted stem cells can replace aging brain cells, restore normal brain function and improve cognitive function and various declined functions of patient s brain. This kind of treatment has definite effects and can improve the life quality of aging people to make them happy.
Advantages of Stem Cell Treatment
Stem Cells, may be pluripotent or multipotent, are important for living organisms for many reasons. Pluripotent stem cells can give rise to any type of cell in the body except those needed to support and develop a fetus in the womb. Stem cells that can give rise only to a small number of different cell types are called multipotent.
Neural Stem Cells (NSCs) are capable to self-renew and differentiate into neurons. When transplanted into the damaged site of brain, NSCs are able to differentiate into corresponding neural cells at the focus, and produce various neurotrophic factors. As the results, the damaged cells will be replaced, the nerve loop will be reconstituted and the degeneration of nerves or semi-apoptotic cells will be inhibited.
The advantages of the stem cells transplantation are followed:
- Relatively safe compare with most of the conventional treatments
- No immunological rejection, since stem cells have very low immunity
- Not affected by the blood-brain barrier, because stem cells are directly injected into the damaged tissues.
Advantages of Fetal Stem Cell Treatment
In the World Stem Cell Therapy Center, the stem cells used for most of our therapies are the Fetal Stem Cells (FSCs). FSCs treatment has a number of advantages compared with the transplantation of any other types of stem cells, i.e. adult, cord blood and animal stem cells.
- Avoid the histocompatibility problems
Histocompatibility has always been regarded as stumbling-block of transplantology, causing rejection of transplanted organs, bone marrow and cord blood stem cells, etc., thus requiring additional special methods aimed at suppression of the recipient’s immune system. With fetal stem cell transplantation, it is possible to avoid any side effects related to histocompatibility and ensure engraftment and proliferation of the administered cells, as well as their functioning in the body for many months and even years without immunosuppression.
- Ensure both target and systemic effects
In addition to targeted cell effects predicted and described by researchers, fetal stem cell transplantation can exert powerful systemic effects related to psychoemotional sphere, physical activity, immune system, homeostasis and functioning of internal organs, achieved via regulatory systems of the recipient’s body. Each type of stem cells produces certain specific tissues. Human regulatory systems, controlling the transplanted cells, guide the development and specialization of those cells in compliance with body needs, thereby ensuring precise specialization of clinical effects. Only natural tissues are used without any genetic engineering or cloning process for the cell cultures. The effects of the FSCs treatments are significantly different from most other medicinal treatments. Within 1 2 months after transplantation, early clinical effects of FSCs transplantation can be observed. The long-term effects of the FSCs treatments can be 6 3 years. In some cases, the engraftment will stay for lifetime.
