Damage in degeneration of the brain

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NEUROLOGICAL DISORDERS

Neurological disorder is the result of damage in degeneration of the brain following the onset of disease. Neurological process results in Alzheimer's disease. The mechanism responsible for neuronal death, focusing on protein aggregation .Neuronal loss is applicable mainly to Alzheimer's disease and Parkinson's disease [1].

ALZHEIMER'S DISEASE

Alzheimer's disease is the most common form of dementia which involves the loss of memory. It is a progressive condition and there is no cure for this condition and the treatment allows slowing down the development. The early stages may begin with loss of memory [3]. Patients eventually lose all cognitive analytical and physical functioning, and this disease is ultimately fatal [2]

The disease commonly begins after age of 65 and that's continued to up with age. Some cases younger people also get Alzheimer's disease, which is less common. About 5% of men and women ages 65 to 74 have Alzheimer's disease[3][1].

It was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906[1].This disease is associated with Brain shrinkage and localised loss of neurones, mainly in the hippocampus and basal forebrain. The Loss of cholinergic neurons in hippocampus and frontal cortex is feature of the disease.

Alzheimer's disease is measured by The Mini Mental State Examination (MMSE). Using this MMSE to identify the type of Alzheimer's disease .An MMSE score of between 10 and 20 is classified as moderate Alzheimer's disease. An MMSE score of between10 to 14 is classified as moderately severe Alzheimer's disease. The MMSE test is not suitable for some people. For these people, health care professionals should assess the severity of this disease using another method suitable for the person's circumstances. [7]

SYMPTOMS OF ALZHEIMER'S DISEASE:

The patients may have vague memory complaints initially, or the patient's significant other may report that the patients is forgetful. Behavioural disturbances may be present in moderate stages. Lossof daily function is common in advanced stages.[7]

Cognitive: Memory loss-poor recall and losing items

  • Aphasia-circumlocution and anomia
  • Apraxia; disorientation
  • Agnosia

Non cognitive: depression, psychotic symptoms, behavioural disturbances,

  • Wandering, repetitive mannerisms and activities

Functional: inability to care for self (dressing, bathing, toileting, and eating)[7],[2]

PATHOGENESIS OF THE ALZHEIMER'S DISEASE:

AD destroys neurons in the cortex and limbic structures of the brain responsible for higher learning, memory, reasoning, behaviour, and emotional control.

  • Mechanisms involved in pathogenesis of Alzheimer's disease:
  • ß-amyloid protein aggregation ,results of formation of plaques. The rare Alzheimer's disease results from mutation in the APP gene, or in presenilin genes, both of which cause increased Aß formulation.
  • hyperphosphorylation of tau protein, results of intracellular Neurofibrillary tangles development and collapse of microtubules
  • inflammatory processes-levels of multiple cytokines and chemokines are formation in AD brains
  • Mitochondrial dysfunction
  • Glutamate and other excitatory amino acid neurotransmitters have been implicated as potential neurotoxins in AD
  • In this process the neurovasculature stop its function
  • Oxidative stress- Serotonergic neurons of the raphe nucliei and noradrenergic cells of the locus ceruleus are also lost in this mechanism mono amino oxidase type B(MAO-B) activity is increased.
  • Loss of cholinergic neurons [2],[7]
  • The main pathological feature of the AD is characterized by the presence of extracellular amyloid plaques and intra cellular neurofibrillary tangles. This results in neuronal dysfunction causes cell death[4]. The formation of NFTs and plaques apper to be caused by interplay between a number of factors, including age, genes and the environmental, NFTs is composed by paired helical filaments.wich are assemble form the microtubule -associated tau protein[5].

AMYLOIDAL PLAQUES: Amyloidal plaques consist of aggregates of Aß fragments of amyloid precursor protein (APP), a normal neuronal membrane protein produced by the action of ß- and ?-secretases[3]. AD is associated with excessive Aß formation, resulting in neurotoxicity. The normal function of the amyloid precursor protein, a single passes transmembrane glycoprotein that localizes to the cell surface.APP undergoes complex pathways. it producing various size fragments. one of these fragment called amyloid beta protein(Aß).most Aß containing 40 and 42 residue. Aß40 is normally produced small amount than Aß42 that form insoluble amyloid plaques in the brains of all Alzheimer's disease[3,6].

NEUROFIBRILLARY TANGLES: The other main biochemical process is Tau, neurofibrillary tangles are composed by protein which came from tau pathway. Tau is a normal constituent of neuron, being associated with intracellular microtubules. In alzhimer disease and other tauopathies, it becomes abnormally phophorylated and is deposited intracellularly as paired helical filaments with a characteristic microscopic appearance when the cells cells die, this filaments aggregates as extracellular neurofibrillary tangles. That tau phosphorylation is enhanced by the presence of Aß plaques[3].

TYPES OF ALZHEMIR'S DISEASE

GENETCS OF ALZHIMER'S DISEASE:

Ad is genetically complex and heterogeneous disorders. Mostly 5% of AD disease is occur in under 65 age that is early onset AD. early on set AD is depend on the three type of genes this three genes cause early onset AD in families-preseniline1(PS1), preseniline2 (PS2) and amyloid precursor protein (AMP). Late onset AD has been associated with public poly morphisum in genes that serve as genetic risk factor for the disease. The apolipoprotein E(ApoE) gene is associated primarily with Late onset AD.[4]

TYPES OF ONSET ALZHEIMER'S:

  1. Late onset Alzheimer's
  2. Early onset Alzheimer's
  3. Familial Alzheimer's.

Usually the last two kind are linked together, as they occur in people under 65 years.[11]

  1. LATE ON SET ALZHEIMER'S:
  2. Common form of disease seen in 90% of Alzheimer patients. Mostly seen in people over the age of 65 and also half the population of people over 85. it seems to affect any person over 65, with no other common link and hence called sporadic Alzheimer's disease.[11] Late onset AD or LOAD. A gene named apolipoprotein E(ApoE) has a positive & negative impact over Alzheimer's development .ApoE is the second AD associated gene to be identified and major risk factor for LOAD. this gene is involved with cholesterol storage ,transport, and metabolism. It is found in both neurons and glial cells and in increase the levels of neuritic plaques. The is form of ApoE are encoded by three alleles labelled e2,e3, and e4. The ApoE e2 and ApoE e3 is may actually protective from AD. The other one ApoE e4 is higher risk of this disease. It seems 50% of LOAD is cases by e4 gene.the other genetic factors for LOAD fond on chromosomal 10,11, and 12 . Illness also can be seen by life style and toxins effect [10],[9].[8]

  3. EARLY -ONSET ALZHEIMER'S:
  4. In early onset mutation of 3 genes as seen genes- preseniline1 (PS1), preseniline2 (PS2) and amyloid precursor protein (APP). The first gene is linked with this form of AD was APP. this has been shows to contain six different pathogenic mutations. Only two to three percent of mutation present in AD. The age of one set of AD mutation is done by APP ranges from 39 to 67.transgenic mice expressing AD mutations in APP produce numerous ß-amyloid deposits in the form of senile plaques.[8] [9]

    PS-1 gene on chromosome was identified in 1995 by positional cloning strategy. PS -2 gene on chromosome was isolated in a group of extensive genetic sequence homology. [9]. These two PS mutations are missense mutation that result in single amino acid substances. Scientists have proposed that the PS -1 gene on chromosomal 14 and the PS-2 gene on chromosomal 1 code for ?-secretase. One of the enzyme is key for formation of the Aß in the first place(ß-secretase is coded for the chromosomal 11). Mostly 40% of easy on set disease is caused by the chromosomal 14. The other early onset genetic mutation has been traced to a gene on chromosome 21that may code for APP. [10]

    Mutations in These genes can cause disease only if they mutate, but are they good in body if they are isolated. Symptoms like memory loss, confusion and difficulties performing simple works are common. A most common symptom seen is myoclonus, which causes muscle twitching and spasms.[11]

  5. FAMILIAL ALZHEIMER'S

It mainly attacks younger people and is a very rare disease. Sometimes seen in people of 30's.it is seen in families with a genetic fault of some chromosomes like 21, 141. In this case the off springs of suffers carries genetically throughout family.[11]

LOSS OF CHOLINERGIC NEURONS

Cholinergic nerve transmission is terminated by the enzyme acetylcholinesterase (AchE). AchE is found both on the post-synaptic membrane of cholinergic synapses and in other tissues eg red blood cells. Acetylcholine (Ach) binds to AchE and is hydrolysed to acetate and choline. This inactivates the Ach and the nerve impulse is halted. AchE inhibitors (eg rivastigmine) prevent the hydrolysis of Ach, which increases the concentration of Ach in the synaptic cleft; AchE inhibitors are widely used in the treatment of Alzheimer's disease.

Fig no4: Choline acetyl transferee's activity, acetylcholine content, and acetyl cholinesterase and choline transport in the cortex and hippocampus are all reduced considerably in AD but not in other disorders, such as depression or schizophrenia. Muscatine receptor density, determined by binding studies, is not affected, but nicotinic receptors, particularity in the cortex, are reduced. The reason for the selective loss of cholinergic neurons resulting from Aß formulation is not know.

ACHANGES IN THE BRAIN IN ALZHEIMER'S DISEASE:

Alzheimer's disease causes the slow, progressive dearth of nerve cells in the cerebral hemispheres of the brain. This disease mechanism begins as many as 10-20 years before and it grownup with age. The first area in which nerve cells die in AD is located near the canter of the cerebral hemispheres that is hippocampus. The brain one part of the enthorhinal cortex develop the tangles due to loss of acetyl choline. and palaques form in other place of brain. as more and more plaques and tangles form in particular brain area, so normal neuron begin to work less efficiency . So, they lose their ability and function and communicate with each other, finally the neurons die. This damaging process spread in the hippocampus. which hippocampus is the memory area of the brain. All memory is catalogued and recorded by in this area. As the death of neurons increases, Effected brain region begin to shrink. By the final stage of AD, damage is widespread and brain tissue has shrunk significantly.[12]

VERY EARLY SIGNS AND SYMPTOMS

Memory problems are one of the first signs of AD. Some people with memory problems have a condition called amnesic mild cognitive impairment (MCI). People with this condition have more memory problems than normal for people their age, but as serves as those with AD.

STAGES OF ALZHEIMERS DISEASE:

MILD AD

Patients have difficulty to remembering recent things. They ability to manage finance, prepare food, and carry out other household activities declines.[7]

MODERATE AD

In this stage, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought. Memory loss and confusion increase, and people begin to have problems recognizing family and friends. They may be unable to learn new things [13]

SEVERE AD

By the final stage, plaques and tangles have spread throughout the brain and brain tissue has shrunk significantly. People with severe AD cannot communicate and are completely dependent on other for their care. Near the end, the persons may be in bed most or all of the time as the body shuts down.[13]

DAIGNOSIS OF ALZHEIMER'S DISEASE:

  • The definitive diagnosis of AD is made by examining brain tissue.
  • MINI MENTAL STATE EXAMINATION: Using this MMSE to diagnose moderate and moderately severe of Alzheimer's disease. The MMSE test is not suitable for some people. For these people, health care professionals should assess the severity of this disease using another method suitable for the person's circumstances.[7]

Several different methods are used to assess the severity of Alzheimer's disease. These include: the clinician's interview -based impression of change (CIBIC) and CIBIC -plus for global outcomes; the progressive deterioration scale (PDS) for functional/quality-of-life scales; and the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog-70 points) or the MMSE (30 points) for cognitive outcomes. MMSE score, for example, donates the severity of cognitive impairment as follows:

  • Mild Alzheimer's disease- MMSE 26-18
  • Moderate Alzheimer's disease -MMSE 17-10
  • Moderately severe Alzheimer's disease -MMSE 10-14
  • Severe Alzheimer's disease-MMSE less than 9-0.[7]
  • Patients with suspected AD should have history and physical examination with appropriate laboratory and other diagnostic tests neurological and psychiatric examinations, standardized rating assessment.[7]
  • Rule out vitamin B12 and folate deficiency, and rule out hypothyroidism with thyroid function tests. CT or MRI scans may aid diagnosis [7]
  • The agency for Healthcare Research and quality [2]
  • The National Institute of Neurological and Communicative Disorders and stroke.[2]

TREATMENT FOR ALZHEIMER'S DISEASE:

NON PHARMACOLOGIC THERAPY

PHARMACOTHERAPY OF COGNITIVE SYMPTOMS

ACETYL CHOLINESTERASE INHIBITORS: The three acetyl cholinesterase inhibitors Galantamine, Rivastigmine and donepezil. Acetylcholinesterase (AChE) inhibitor increases in the concentration of acetylcholine at site of neurotransmission. Donepezil, galantamine and rivastigmine foe mild to moderately severe Alzheimer's disease The benefits of these drugs for patients with other form of dementia For example, vascular dementia, dementia with lewy bodies7.

DONEPEZIL:

Donepezil is a drug that is used to help improve the condition of people suffering from Alzheimer's disease. It is found to increase a naturally occurring substance in the brain, specifically the cortical acetylcholine. Donepezil is marketed under the brand name Aricept.

Donepezil is a piperidine derivative with specificity for inhibition of acetyl cholinesterase rather than butyrylcholinesterase.

It is approved for treatment cognitive impairment in mild to moderately. Severe AD (MMSE score10 to 26). Patients taking donepezil had improved cognition for the first 6 to 9 months.

Donepezil has the following structural formula:

  • Molecular formula of donepezil is C24H29NO3
  • Molecular weight is 379.492 g/mol
  • Donepezilavailable:5mgtablets,10mgtablets

Donepezil is available in tablet forms. Aside from the regular tablet, there are also disintegrating tablets that quickly dissolve in the tongue8.

ARICEPT: donepezil (Aricept , Eisai) is a specific and reversible inhibitor of AChE, Licensed in the UK at a dosage of 5 mg /day and 10 mg/day. It is licensed for the symptomatic treatment of people with mild and moderately severe Alzheimer's dementia9.

  • Section: central nervous system
  • Sub section: Alzheimer's disease
  • Drug class: Anticholinesterases
  • Drug name: Donepezil10

DRUG CLASS MECHANISAM: This drug belongs to a group of medicines called acetyl cholinesterase inhibitors. Donepezil increases the levels of a acetylcholine in the brain involved in memory function by slowing down the breakdown of acetylcholine. It is used to treat the symptoms of dementia in people diagnosed as having mild and moderately11.

  • FREQUENCY AND TIMING OF DOSES: once daily at bed time
  • ADULT DOSAGE RANGE: 5-10mg
  • ONSET OF EFFECT: 1 hour Full effect may take up to 3 months
  • DURATION of ACTION: usually 1-2 days12
  • DRUG INTERACTIONS:

MUSCLE RELAXANTS USED IN SURGERY: donezepil may increases the effect of some muscle relaxants,but it may also block some others.

Fluoxetine, erythromycin and ketoconazole can increase the levels and adverse effects of donepezil13.

ADVESRSE EFFECTS:

  • Central nervous system: Insomnia(6%-14%),
  • Gastrointestinal: Nausea, Diarrhea, Vomiting
  • Cardiovascular : Chest pain, Hyper tension
  • Central nervous system: Abnormal dreams, Depression, Dizziness, Headache.

DOSAGE FORMS:

Tablets, as hydrochloride: 5 mg, 10mg14

GALANTAMINE: Galantamine (Reminyl, Shire pharmaceuticals) is a selective, competitive and reversible inhibitors of AChE, licensed in the UK. It is licensed for the symptomatic treatment of people with mild to moderately severe dementia of the Alzheimer's type. In addition , galantamine enhances the intrinsic action of acetylcholine on nicotinic receptors, probably through binding to an allosteric site of the receptor15.

Galantamine has the following structural formula:

  • Molecular formula of galantamine: C17H21NO3
  • Molecular weight is :287.354 g/mol
  • Galantamine available : reminyl, reminyl xl16

DRUGS CLASS AND MECHANISM:

Galantamine is an oral medication used to treat patients with Alzheimer's disease. Galantamine belongs to the class of drugs called cholinesterase inhibitors. Cholinesterase inhibitors inhibit the action of acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine. Acetylcholine is one of several neurotransmitters in the brain, chemical that nerve cells use to communicate with one another. Reduced levels in the brain are believed to be responsible for some of the symptoms of Alzheimer's disease. By blocking the enzyme that destroys acetylcholine, Galantamine increases the concentration of the acetylcholine in the brain, and this increase is believed to be responsible for the improvement in thinking.

  • Section: central nervous system
  • Subsection: Alzheimer's disease
  • Drug class: Anticholinesterases
  • Drug name: galantamine
  • Manufacture: shire pharmaceuticals Ltd.
  • PREPARATIONS: Reminyl (galantamine)
  • Reminyl Oral Solution
  • Reminyl XL (galantamine)18
  • FREQUENCY AND TIMING OF DOSES: once daily at break fast
  • ADULT DOSE RANGE: 5- 8 mg
  • DURATION OF ACTION: 1 to 2 days 19

DRUG INTERACTIONS: Drugs with anticholinergic properties and which cross into the brain, such as atropine .trihexy phenidyl (artane) produce opposite effects of (counteract) galantamine and should be avoided during therapy with galantamine.

SIDE EFFECTS: Nausea, vomiting, diarrhoea, dizziness, decreased appetite or weight loss may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly20.

RIVASTIGMINE: (Exelon) has central activity at acetylcholinesterase and butyrylcholinesterase sites, but low activity at these sites in the periphery. Theoretically, this should result in fewer peripheral side effects21.

Rivastigmine has the following structural formula:

  • Molecular formula of rivastigmine:C14H22N202
  • Molecular weight:250.337 g/mol
  • Rivastigmine available in: Exelon22

EXELON:

(Exelon ,Novartis pharmaceuticals UK) is an AChE and butyrylcholinesterase inhibitor, licensed in the UK. It is licensed for symptomatic treatment of people with mild to moderately severe Alzheimer's dementia23.

  • Section: central nervous system
  • Sub section: Alzheimer's disease
  • Drug class: anticholinesterases
  • Manufacture: Novartis pharmaceuticals UK Ltd24
  • FREQUENCY AND TIMING OF DOSES: twice daily
  • ADULT DOSE RANGE: 3mg daily (starting dose), 6-12mg daily(maintenance dose)
  • ONSET OF ETTECT: 30 -60 minutes. Full effect may take up to 3 months
  • DURATION OF ACTION: 9 to 12 hours25.

DRUG CLASS AND MECHANISM:

Rivastigmine is an oral preparation used to treat patients with Alzheimer's disease. This belongs to the class of cholinesterase inhibitors. It inhibits the action of acetylcholine esterase enzyme which is responsible for the destruction of acetylcholine. Reduced levels of acetylcholine in the brain shows the symptoms of Alzheimer's disease. By blocking the enzyme that destroys acetylcholine, Rivastigmine increases the concentration of acetylcholine in the brain21.

PREPARATIONS: Exelon (Rivastigmine)

Exelon oral solution

Exelon transdermal patch26

DRUG INTERACTIONS:

Drug with anticholinergic effects and which cross into the brain, like atropine, benztropine and trihexyphenidyl oppose the effects of Rivastigmine and should be avoided during therapy with Rivastigmine.

Unlike donepezil, Rivastigmine dose not cause the blood levels of medications to rise and increase their risk for side effects23.

SIDE EFFECTS: Central nervous system: dizziness(21%), headache(17), Gastrointestinal: nausea, vomiting, diarrhea Neuromuscular &skeletal: weakness, tremor27

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