Alzheimer's: A lethal form of dementia (T K Sahu)

Alzheimer’s disease (AD), one form of dementia, can be a degenerative brain disease characterized by progressive cognitive deterioration as well as declining activities of daily living as well as neuropsychiatric symptoms or behavioral improvements. which affects memory, thinking, behaviour, language, decision-doing ability, judgment, attention, as well as additional areas of mental function as well as personality. The rate of progression varies coming from individual to individual. The AD may grow slower or faster depending upon the patient however ultimately which results deterioration of both mental as well as physical health.

Affected Areas

The frontal as well as   temporal lobe of brain are primarily affected by Alzheimer’s. Temporal lobe can be associated with auditory procession. The hippocampus, a part of brain located under the temporal lobe forming the part of limbic system can be primarily injured by Alzheimer’s. Generally, the microtubule system of  hippocampus as well as  neocortex(part of  cerebral cortex forming the top layer of cerebral hemisphere as well as involved in sensory perception ,generation of  motor  commands spatial reasoning conscious thought as well as in human language)can be disrupted as well as replaced by  neurofibrillary tangles of  paired helical filaments. Mostly the neurons of cerebral cortex are heavily affected by Alzheimer’s. The hypothalamus as well as the entorhinal cortex (EC, forms the main input to the hippocampus as well as can be responsible for the pre processing of the input signals) can be also affected at later stages.

History

The real history of Alzheimer’s starts with Dr Alois Alzheimer who discovered which disease as well as in a 51 aged female Mrs.  Auguste D. In 1991 Dr Alzheimer noticed the disease in his patient Mrs. Auguste D.  named which as “amnestic writing” disorder. After  few  years which case was  presented inside 37th Assembly of Southwest German Psychiatrists by Dr Alzheimer as well as his colleagues. Later on the disease was known as Alzheimer’s Disease (AD) or simply Alzheimer’s.

For most of the twentieth century, the diagnosis of Alzheimer’s disease was reserved for individuals between the ages of 45-65 who developed symptoms of pre-senile dementia due to the histo-pathologic process discovered by Dr. Alzheimer. During which time senile dementia itself was considered to be a more or less normal outcome of the aging process, as well as thought to be due to age-related brain arterial “hardening.” inside 1970s as well as early-1980s, because the symptoms as well as brain pathology were identical for Alzheimer victims older as well as younger than age 65, the name “Alzheimer’s disease” began to be used, within as well as outside the medical profession, equally for afflicted individuals of all ages, although in which period the term senile dementia of the Alzheimer type (SDAT) was often used to recognize those over 65 who did not fit the classical age criterion. Eventually, the term Alzheimer’s disease was adopted formally inside psychiatric as well as neurological nomenclature to describe individuals of all ages with the characteristic common symptom pattern, disease course, as well as neuropathology. The term Alzheimer disease also continues to be used commonly inside literature.

Types

Based on genetics, Alzheimer’s can be of two basic types; familial as well as sporadic

  1. Familial Alzheimer’s Disease (FAD): which rare type can be caused by a genetic mutation. which can be the result of abnormal processing of APP as well as which occurs because the gene which makes APP can be abnormal, or because a gene which makes the presenilins, which are responsible for processing APP, can be abnormal. The age of onset can be earlier than for sporadic Alzheimer’s disease, with symptoms appearing when the person can be aged in their 40s or 50s. familial Alzheimer’s disease
  2. Sporadic Alzheimer’s Disease (SAD): which can be called ‘sporadic’ because which appears in families with little or no family history of the disorder. which can be due to the relationship between any one gene as well as the presence of disease can be weaker than in familial Alzheimer’s disease .The situation can be similar to the relationship between smoking as well as lung cancer. Smoking greatly increases the risk of lung cancer, however not everyone who smokes develops lung cancer. Genes which behave like which are often called susceptibility genes, as well as which pattern of inheritance can be often called complex. Complex inheritance means which there are usually many genes, all variously contributing in a tiny way, acting in concert to produce a high risk of developing a disease. Sporadic AD appears to be related to the ApoE gene found on chromosome 19. Sporadic AD accounts for more than 0 per cent of cases. Adult men as well as women of all ages can be affected, although most cases occur in people over the age of 65 years. which can take up to 20 years for the disease to develop.

Based on the age again which can be of two types: early onset as well as late onset

  1. Early onset:  In early onset AD, symptoms first appear before age 60. Early onset AD can be much less common, accounting for only 5-10% of cases. However, which tends to progress rapidly. Early onset disease can run in families as well as involves autosomal dominant, inherited mutations which may be the cause of the disease. So far, three early onset genes have been identified.
  2. Late onset: Late onset AD, the most common form of the disease, develops in people 60 as well as older as well as can be thought to be less likely to occur in families. Late onset AD may run in some families, however the role of genes can be less direct as well as definitive. These genes may not cause the problem itself, however simply increase the likelihood of formation of plaques as well as tangles or additional AD-related pathologies inside brain.

 Stages 

  1. Mild: At the early stage of the disease, patients have a tendency to become less energetic or spontaneous, though improvements in their behavior often go unnoticed even by the patients’ immediate family.
  2. Moderate: As the disease progresses to the middle stage, the patient might still be able to perform tasks independently, however may need assistance with more complicated activities.
  3. Severe: As the disease progresses coming from the middle to late stage, the patient will undoubtedly not be able to perform even the simplest of tasks on their own as well as will need constant supervision. They may even lose the ability to walk or eat without assistance. They might forget to eat as well as starve.

Symptoms

As Alzheimer can be a progressive disease the symptoms are noticed in all its stages however inside early stages, the symptoms of AD may be subtle as well as resemble signs which people mistakenly attribute to “natural aging.” Symptoms often include:

  • Memory lapses
  • Problems with thinking of the right word for common objects
  • Confusion , wandering
  • Personality improvements, such as irritability, frustration, anxiety
  • Repeating statements
  • Misplacing items
  • Having trouble finding names for familiar objects
  • Getting lost on familiar routes
  • Losing interest in things previously enjoyed
  • Difficulty performing tasks which take some thought, however used to come easily, like balancing a checkbook, playing complex games (such as bridge), as well as learning brand-new information or routines

In a more advanced stage, symptoms are more obvious:

  • Forgetting details about current events
  • Difficulties with doing decisions
  • Forgetting events in your own life history, losing awareness of who you are
  • Problems choosing proper clothing
  • Hallucinations, arguments, striking out, as well as violent behavior
  • Delusions, depression, agitation
  • Difficulty performing basic tasks like preparing meals as well as driving

At end stages of AD, a person can no longer survive without assistance. Most people in which stage no longer:

  • Understand language
  • Recognize family members
  • Perform basic activities of daily living such as eating, dressing, as well as bathing
  • Long term memory loss, including forgetting the names of family members
  • Inability to manage responsibilities, such as work or running the house
  • Impaired judgment or concentration
  • Impairment of reasoning as well as thinking skills
  • Inability to look after oneself; for example, help may be needed to go to the toilet
  • Severe personality improvements
  • Loss of social skills, such as the ability to hold a conversation
  • Speech loss
  • Disruptive behavior
  • Hallucinations
  • Aggression
  • Suspiciousness or paranoia
  • inside later stages, the person can be usually bed-ridden as well as needs full-time care.

Causes

The cause of AD can be not entirely known however can be thought to include the genetic, biochemical as well as environmental factors.

Genetic Factors

Rare cases of Alzheimer’s are caused by dominant genes which run in families. These cases often have an early age of onset. Mutations in presenilin-1 or presenilin-2 genes have been documented in some families. Mutations of presenilin1 (PS1) lead to the most aggressive form of familial Alzheimer’s disease (FAD). Evidence coming from rodent studies suggests which the FAD mutation of PS1 results in impaired hippocampal-dependent learning which can be correlated with reduced adult neurogenesis inside dentate gyrus. Mutations inside APP gene on chromosome 21 can also cause early onset disease. The presenilins have been identified as essential components of the proteolytic processing machinery which produces beta amyloid peptides through cleavage of APP.

Inheritance of the ε4 allele of the ApoE gene can be regarded as a risk factor for development of disease, however large-scale genetic association studies raise the possibility which even which does not indicate susceptibility so much as how early one can be likely to develop Alzheimer’s. There can be speculation among genetic experts which there are additional risk as well as protective factor genes which may influence the development of late onset Alzheimer’s disease (LOAD). Researchers are investigating the possibility which the regulatory regions of various Alzheimer’s associated genes could be important in sporadic Alzheimer’s, especially inflammatory activation of these genes. These hypotheses include the amyloid-β precursor protein (APP), the beta secretase enzymes, insulin-degrading enzyme, endothelin-converting enzymes, as well as inflammatory    5-lipoxygenase gene. Alzheimer’s disease can be definitely linked to the 1st, 14th , as well as 21st chromosomes, however additional linkages are controversial as well as not, as yet, confirmed. While some genes predisposing to AD have been identified, such as ApoE4 on chromosome 19, sporadic AD also involves additional risk as well as protective genes still awaiting confirmation.

Biochemical Factors

The biochemical factors include various hypotheses such as amyloid hypothesis, cholinergic hypothesis as well as Tau hypothesis etc. The amyloid hypothesis explains about the deposition of β-amyloids inside brain where as the cholinergic hypothesis describes about the reduced level of neurotransmitter acetylcholine as well as the tau hypothesis describes about neurofibrillary tangle deposition in brain causing Alzheimer’s.

Amyloid Hypothesis

 According to which hypothesis the Amyloid precursor protein (APP) can be cleaved by β-secretase as well as γ-secretase to form the β-amyloids. These β-amyloids results the formation of senile plaques which blocks the signal transmission. Beta-Amyloid (Aß) peptides, made up of long, insoluble ordered fibers, are glycol-proteins deposited extracellular in tissues in amyloidosis. These peptides are generated as cleavage products 39 to 43 amino acids in length coming from the membrane protein, Amyloid Precursor Protein (APP) by two proteases, ß-secretase as well as γ-secretase. Aßs are amphiphilic peptides using a hydrophilic N-terminal domain (residues 1 to 28) as well as a hydrophobic C-terminal (residues 29 to 40), the latter corresponding to a part of the transmembrane domain of APP. Heterogeneity at both ends of the peptides can be known to affect the toxicity of beta-amyloid peptides. Amyloid deposits are insoluble as well as the core component of these plaques can be Aß peptides which are 39 to 42 amino acid residues in length using a molecular mass of approximately 4 kDa. ß-Amyloid assembly into fibrils can be initiated by a conformational transition coming from random coil to ß-sheet as well as a nucleation-dependent aggregation process.

Tau Hypothesis

AD can be histopathologically characterized by intra-neuronal accumulation of paired helical filaments forming neurofibrillary tangles. Tau hypothesis describes about the formation of these neurofibrillary tangles by the hyperphosphorylation of tau protein. Tau proteins are microtubule-associated proteins which are abundant in neurons inside central nervous system as well as are less common elsewhere. They were discovered in 1975 in Marc Kirschner’s laboratory at Princeton University (Weingarten et al., 1975).

AD can be considered a tauopathy due to abnormal aggregation of the tau protein. Like most microtubule-associated proteins, tau can be normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulated as paired helical filaments which in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles (NFT) as well as as dystrophic neurites associated with amyloid plaques. The normal tau generally binds to tubulin in its microtubule-binding repeat region however when which gets hyperphosphorylated by the increased activity of kinases then which form anti parallel dimers of microtubule-binding repeat region (MBRR) (Warren J strittmatter et al., 1994),as a result of which the hyperphosphorylated tau competes with tubulin to bind with normal tau as well as forms paired helical filaments (PHF) causing disruption of performed microtubule (Iqbal K et al.) .These paired fragments further associated to form the NFTs. These NFTs blocks neuronal transmission resulting neuronal death as well as finally results the Alzheimer’s.

Cholinergic hypothesis

The cholinergic hypothesis can be generally based on the reduced level of neurotransmitter acetyl choline as well as death of cholinergic neurons. The chemical compound acetylcholine, often abbreviated as ACh, was the first neurotransmitter to be identified. which can be a chemical transmitter in both the peripheral nervous system (PNS) as well as central nervous system (CNS) in many organisms including humans.

Normally, the enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline as well as acetate. The shortage of acetylcholine inside brain has been associated with Alzheimer’s disease, some drugs which inhibit acetylcholinesterase are used inside treatment of which disease. A recent study has shown which THC can be one such drug, effective at reducing the formation of characteristic neurofibrillary tangles as well as amyloid beta plaques.

Environmental Factors

In one set of studies aluminum absorption can be 2-3-fold higher in Alzheimer’s patients as compared to aged-matched controls as well as 6-fold higher in Down’s syndrome, a condition having the pathologic hallmarks of AD. In July 1988, 20 tonnes of aluminium sulphate was dischargedby the South West Water Authority into the drinking water suppliedto a large region ofNorth Cornwall. Up to 20 000 people wereexposed to concentrations of aluminium which were 500–3000times the acceptable limit under European Union legislation(0.0 mg/l). Although which incident can be currently the topicof a government inquiry, nothing can be known about its longer-termrepercussions on human health. The first neuropathological examinationof a person who was exposed as well as died of an unspecified neurologicalcondition was carried out. A rare form of sporadic early-onsetß amyloid angiopathy in cerebral cortical as well as leptomeningealvessels, as well as in leptomeningeal vessels over the cerebellum wasidentified. In addition, high concentrations of aluminium werefound coincident with the severely affected regions of the cortex.Although the presence of aluminium can be highly unlikely to beadventitious, determining its role inside observed neuropathologyis impossible. A clearer understanding of aluminium’srole in which rare form of Alzheimer’s related diseaseshould be provided by future research on additional people coming from theexposed population as well as similar neuropathologies in peoplewithin or outside which group. According to some journal a 58-year-old woman using a rapidly progressive,fatal dementing illness, who, at autopsy, shows dramatic ß-amyloiddeposition of cerebral cortical as well as leptomeningeal blood vessels,modest numbers of neurofibrillary tangles as well as Lewy bodies, andevidence of very high aluminium content in affected brain regions.Of particular interest can be which she was among the 20 000 peoplewho were accidentally exposed, in July 1988, to exceedinglyhigh concentrations of aluminium in their water supply in theso-called “Camelford incident”. which can be the first autopsy-documentedcase of Alzheimer’s disease-like neurodegeneration ina victim of which incident. Copper can be another candidate as Dr. Rosanna Squitti was the first to discover the link between the fraction of copper not bound to serum ceruloplasmin, referred to as non-ceruloplasmin-copper (NCC), as well as the clinical picture of Alzheimer’s disease. Copper may increase the growth of the protein clumps inside brain which are a trademark of Alzheimer’s disease, according to a brand-new US study on rabbits. inside latest experiments, the cholesterol-fed rabbits were given water laced with 0.12 parts per million copper, one tenth ofUSsafety limit for humans. Three-quarters of the rabbits showed senile plaque-like deposits in their brains after 10 weeks. These rabbits also showed an 80 per cent deficit in memory in complex conditioning tests. The plaques were not found inside brains of animals given pure distilled water as well as were rare among those drinking tap water.”Although we can only speculate about how the effects of copper consumption in cholesterol-fed rabbits relate to those in humans, which can be of note which the levels of copper, which induced beta-amyloid as well as senile plaque-like structures are well below those considered safe for humans.

In addition, which has been shown which quite a few organic acids, such as lactic, gluconic, malic, citric as well as oxalic acids significantly increase aluminum absorption as well as deposition inside brain.

Risk factors for alzheimer’s

  • Advancing age
  • Reduced testosterone levels.
  •  ApoE epsilon 4 genotype (in some populations)
  • Poor cardiovascular health (including smoking, diabetes, hypertension, high cholesterol
  • Exposure to light metals in particular Aluminum can be a proposed however not widely-accepted risk factor. Aluminium, a neurotoxin, can be often present in higher quantities in brains of Alzheimer’s patients, as well as the relationship between aluminum as well as Alzheimer’s can be building.
  • Longstanding high blood pressure
  • History of head trauma
  • High levels of homocysteine (a body chemical which contributes to chronic illnesses such as heart disease, depression, as well as possibly AD)
  • Female gender — because women usually live longer than men, they are more likely to develop AD

Risk Reducers

  • Regular physical exercise
  • Regular social interaction
  • A Mediterranean diet with fruits as well as vegetables as well as low in saturated fat, supplemented in particular with:
    • B vitamins
    • Omega-3 fatty acids, especially Docosahexaenoic acid
    • Fruit as well as vegetable juice
    • High doses of the antioxidant Vitamin E (in combination with vitamin C) seem to reduce Alzheimer’s risk in cross sectional studies however not in a randomized trial as well as so are not currently a recommended preventive measure because of observed increases in overall mortality
  • Cholesterol-lowering drugs (statins) reduce Alzheimer’s risk in observational studies however so far not in randomized controlled trials
  • Female Hormone replacement therapy can be no longer thought to prevent dementia based on data coming from the Women’s Health Initiative
  • Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs), used to reduce joint inflammation as well as pain as well as  can be associated using a reduced likelihood of developing AD, according to some observational studies. The risks appear to outweigh the drugs’ benefit as a method of primary prevention.
  • Recent medical research has found which cannabinoids, the psychoactive compounds in marijuana, “succeed in preventing the neurodegenerative process occurring inside disease.”

Treatments

There can be currently no cure for Alzheimer’s disease. Currently available medications offer relatively tiny symptomatic benefit for some patients however do not slow disease progression. The American Association for Geriatric Psychiatry published a consensus statement on Alzheimer’s treatment in 2006.

Inhibitors of Acetylcholinesterase

Acetylcholinesterase (AChE) inhibition was thought to be important because there can be a reduction in activity of the cholinergic neurons. AChE-inhibitors reduce the rate at which acetylcholine (ACh) can be broken down as well as hence increase the concentration of ACh inside brain (combating the loss of ACh caused by the death of the cholinergic neurons). Acetylcholinesterase-inhibitors seemed to modestly moderate symptoms however do not alter the course of the underlying dementing process.Mainly used acetylcholinesterase inhibitors are tacrine (no longer clinically used), donepezil (marketed as Aricept), galantamine (marketed as Razadyne inside U.S.A. Marketed as Reminyl or Nivalin inside rest of the globe), as well as rivastigmine (marketed as Exelon). There can be significant doubt as to the effectiveness of cholinesterase inhibitors. quite a few recent articles have criticized the design of studies reporting benefit coming from these drugs, concluding which they have doubtful clinical utility, are costly, as well as confer many side effects. The pharmaceutical companies, however also some independent clinicians, dispute the conclusions of these articles.

A Natural Extract, As a Drug

One of the natural extracts which has been examined in Alzheimer’s can be Ginkgo (Ginkgo biloba), also known as the Maidenhair Tree. The extract of the Ginkgo leaves contains flavonoid glycosides as well as terpenoids, as well as both seeds as well as leaves have been used pharmaceutically in China as well as the West. Examining over 50 studies conducted on Ginkgo for the treatment of “cognitive impairment as well as dementia,” a Cochrane Review concludes which “there can be promising evidence of improvement in cognition as well as function associated with Ginkgo.” According to which review the two randomized controlled studies which focused on Alzheimer’s patients both showed significant improvement in these areas. The review calls for a large study which can “provide robust estimates of the size as well as mechanism of any treatment effects”.The AAGP review did not recommend Ginkgo neither did which warn against its use. A large, randomized clinical study inside US called the GEM study can be underway (fully enrolled) as well as examining the effect of Ginkgo to prevent dementia.

Antagonists of NMDA

Recent evidence of the involvement of glutamatergic neuronal excitotoxicity causes Alzheimer’s disease led to the development as well as introduction of memantine. Memantine can be a novel NMDA receptor antagonist, as well as has been shown to be moderately clinically efficacious. Memantine can be marketed as Akatinol, Axura, Ebixa as well as Namenda.

Treatments in clinical development

A large number of potential treatments for Alzheimer’s disease are currently under investigation, Vaccines or immunotherapy for Alzheimer’s, unlike typical vaccines, could be used to treat diagnosed patients rather than for disease prevention. Ongoing efforts are based on the idea which, by training the immune system to recognize as well as attack beta-amyloid, the immune system might reverse deposition of amyloid thereby stop the disease. Initial results using which approach in animals were promising, as well as human-trials of drug AN-1792 showed results in 20% of patients; however, 6% of multi-dosed participants (18 of 300) developed encephalitis in 2002, as well as the trials were stopped. Participants inside halted trials continued to be followed, as well as 20% “developed high levels of antibodies to beta-amyloid” as well as some showed slower progression of the disease, maintaining memory-test levels while placebo-patients worsened. Work can be continuing on less toxic Aβ vaccines, such as a DNA-based therapy which recently showed promise in mice. Researchers fromUniversity of SouthFloridaannounced a patch type of the drug was shown to be safe as well as effective when tested on mice. Proposed alternative treatments for Alzheimer’s include a range of herbal compounds as well as dietary supplements. Vitamin E in doses below 400 IU was mentioned as having conflicting evidence in efficacy to prevent AD. Higher doses were discouraged as these may be linked with higher mortality related to cardiac events. Laboratory studies with cells as well as animals continually fuel the pipeline of potential treatments. Some currently approved drugs such as statins as well as thiazolidinediones have also been under investigation for the treatment as well as prevention of Alzheimer’s. Recent clinical trials for Phase 2 as well as Phase 3 in which category have taken 12 to 18 months under study drug, plus additional months for patient enrollment as well as analysis. Compounds which are just entering into human trials or are in pre-clinical trials could be at least 4 years coming from being available to the public as well as could be available only if they can demonstrate safety as well as efficacy in human trials.

Alzheimer's: A lethal form of dementia (T K Sahu)

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