Alzheimer's - GN0453

8/3/2019 Alzheimer's - GN0453

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ALZHEIMER’S DISEASE

BY:-

AISHWARYA SINGH

11408005B.Tech GENETIC ENGINEERING

S.R.M UNIVERSITY



INTRODUCTION

•Alzheimer’s disease is a neurological brain disorder namedafter a German physician, Alois Alzheimer, who firstdescribed it in 1906.

•It is the most common form of dementia which destroys thebrain cells slowly and prgressively , eventually interfereingwith many aspects of brain functions.

•Memory loss is one of the most earliest symptoms which

gradually leads to widespread loss of mental abilities due towhich people depend on others for every aspect of theircare.

•It is marked by plaques and neurofibrillary tangles in braincells due to which the areas associated with the intellectual



HISTORICAL BACKGROUND

•It was in 1901 that German psychiatrist Alois Alzheimeridentified the first case of Alzheimer's disease in a fifty-year-oldwoman Auguste D.

•When she died in 1906 her brain was sent to him forexamination and then it was in 1907 that he published his talk.

•The autopsy reveald the most serious form of dementia ,almost one-third of the cortical cells had died off. In their placeinstead they found peculiar deeply stained fibrillary bundles thatwere closely packed to one another, and seemed to be

remnants of degenerated cell bodies.



ANALYSIS OF BRAIN

There are threeinterconnected levels ofhuman brain:-• The brain stem andcerebellum•The limbic system•The cerebral cortex

The brainstem controlsheart beat and body

temperature.Cerebellum controls bodymovements.

The limbic system controls

emotions .It is also centerto memory and learning.



The hippocampus, is active in converting information into

long-term memory and in memory recall. Damage to thehippocampus or its nerve connections can cause amnesia.

The amygdala, is concerned with emotional memory. But

damage to the amygdala can abolish an emotion-chargedmemory.

In Alzheimer's disease, brain cells die and neuronalconnections wither in all parts of the brain, but especially inthe hippocampus and the amygdala.





GENERAL SYMPTOMS OF

ALZHEIMER’S DISEASE

•Loss of abstract thinking•Disorientation

•Lack of initiative•Language problems•Missplacing items

•Mood swings•Personality changes•Poor judgement



CLINICAL SYMPTOMS

Microscopyimage of

neurofibrillary

tangle, conformedby

hyperphosphorylated tau protein

Amyloid plaques: deposition of amyloid beta ( Aβ)

in brain tissue.

Neurofibrillary tangles: formation of neurofibrillarytangles by hyperphosphorylated of tau proteins.

Neuronal loss: loss of nerve cells.

Gliosis: Glial cells are non-neuronal cells .Astrocytes are nothing but relatively large glial cells.Gliosis is a proliferation of astrocytes in damaged

areas of the central nervous system (CNS) whichcauses CNS injury.

Cholinergic depletion: reduced synthesis of theacetylcholine.

Shrinkage of brain: reduction in brain size



The role of amyloid plaques in Alzheimer's

Amyloid plaques are mostly made up of a protein calledB-amyloid protein which is itself part of a much largerprotein called APP (amyloid precursor protein).

We do not know exactly what APP does. But we doknow that APP is made in the cell, transported to the cell

membrane and later broken down.

In Alzheimer's disease, the fragments accumulate toform hard, insoluble plaques.



Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is thought to be important for neuronal growth, survival, and repair.



Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or

Ab.



Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming the plaques seen in the AD brain.



Neuronal Plaques in Alzheimer’s Disease



The role of Neurofibrillary tangles

These are insoluble twisted fibers found inside the brain'scells.

These tangles consist primarily of a protein called tau,which forms part of a structure called a microtubule.

The microtubule helps transport nutrients and otherimportant substances from one part of the nerve cell to

another.

In people with Alzheimer's tau proteins cause abnormalitythrough overactive enzymes resulting in the formation of

neurofibrillary tangles. Neurofibrillary tangles result in thedeath of the cells.







SEVERITY OF THE DISEASE

Early dementiaDifficulties with language, executive functions, and execution ofmovements are more prominent than memory problems. Older memoriesare affected to a lesser degree than new memories. They find difficulty inwriting or dressing but they are commonly unnoticed.

Moderate dementiaPatients are unable to perform most common activities of daily living.

Speech difficulties become evident and reading and writing skills are alsolost. The person may fail to recognise close relatives. Long-term memorybecomes impaired.

Advanced dementiaDuring this last stage of AD, the patient is completely dependent uponcaregivers. Language is reduced to simple phrases or even single words,eventually leading to complete loss of speech.



1. Pre clinical AD

2. Mild AD

3. Severe AD

12

3





PREVALANCE OF THE DISEASE

In India percentage of Alzheimerpatients is 4 per cent as comparedto United States.

In India, prevalence of dementiais 33.6 per 1000.

In India, Alzheimer's diseaseamong 70- to 79-year olds is 4.4-fold less than that of the UnitedStates.

WHO says ―there are currentlyabout 18 million people worldwidewith Alzheimer’s disease,‖ which

will double by 2025 to 34 million.

Much of this increase will be due

to the ageing population.



EMINENT PERSONALITIES WITHALZHEIMER’S

Ronald Reagan (1911-2004),40th President of the United

States

CharltonHeston (October 4,

1923 – April 5, 2008) was

an American actor of film



GENETIC BASIS OF THE

DISEASE

The exact Genetic cause of of Alzheimer's disease is not known.

Common forms of certain genes increase the risk of developingAlzheimer's disease.

The best-studied gene is the one that encodes apolipoprotein E (apoE)(found on chromosome 19) , a protein that helps carry blood cholesterol .It is found in neurons and other supportive brain cells (called glia) ofhealthy brains.

The apoE gene has three different forms (alleles) -- apoE2, apoE3, andapoE4. The apoE4 form of the gene has been associated with increasedrisk of Alzheimer's disease in most (but not all) populations studied.

At least one copy of the E4 gene is found in 40% of patients withsporadic or late-onset Alzheimer's disease.



The more APOE e4 alleles one inherits, the lower the age of disease

onset.

The relatively rare APOE e2 allele may protect some people against thedisease: It seems to be associated with a lower risk for Alzheimer's and alater age of onset if the disease does develop.

APOE e3 is the most common version found in the general populationand may play a neutral role in Alzheimer's risk.

APOE e4 increases the risk of developing Alzheimer's, but it does notcause the disease. The ways in which APOE e4 increases the likelihood ofdeveloping Alzheimer's are not known with certainty.



Some studies have found that Alzheimer's disease occurs moreoften among people who suffered significant traumatic head

injuries earlier in life, particularly among those with the apoE 4 gene.

Most researchers believe that APOE testing is useful for studyingAlzheimer's disease risk in large groups of people but not for

determining any one person's specific risk.

Most experts believe that additional genes may influence thedevelopment of late-onset Alzheimer’s in some way.

Researchers have identified variants of the SORL1, CLU, PICALM,and CR1 genes that may play a role in risk of late-onset Alzheimer’s



Studies have found that women have a higher risk for Alzheimer'sdisease than men.

The apparent increased frequency of Alzheimer's disease in womenhas led to considerable research about the role of estrogen in

Alzheimer's disease.

Recent studies suggest that estrogen should not be prescribed topost-menopausal women for the purpose of decreasing the risk of

Alzheimer's disease.

Nonetheless, the role of estrogen in Alzheimer's disease remains anarea of research focus.



DIAGNOSTICS

It is impossible to be certain about Alzheimer’s disease diagnosis unless

a sample of brain tissue (a biopsy) or a postmortem examination of thebrain reveals the presence the plaques tangles.

However, with current testing methods, a skilled doctor can correctlydiagnose Alzheimer’s disease in about 90% of cases without performing

a biopsy.

Diagnosing Alzheimer's disease is a process of elimination.

Doctors must rule out other natural causes, such as malnutrition or clinicaldepression.They check the thyroid, to rule out problems there.

In many cases, symptoms of depression can be mistaken for Alzheimer's— and vice versa.



The following things may be used to help make a diagnosisof Alzheimer's disease:

Patient History

A history from the patient helps the doctor assess a person'spast and current health situation.

Mini-Mental State Exam (Neuropsychological Testing)

A mini-mental state exam is a very brief test that the doctor

can use to test a person's problem solving skills, attentionspan, counting skills and memory. It will give the doctorinsight into whether there has been damage to differentareas of the brain.



Chest X-ray

An X-ray is a test in which an image of the body is created by using low doses of

radiation. X-rays can be used to diagnose a wide range of conditions, frombronchitis to broken bones. This test may be used by the doctor to help rule outother disorders that may be causing symptoms similar to those of Alzheimer'sdisease.

Laboratory Tests

The most common are blood tests and urinalysis.

Blood tests may also be used to look for the presence of a specific gene that hasbeen identified as a risk factor for Alzheimer's disease.

A urinalysis is a test in which a urine sample is evaluated to detect abnormalities,such as abnormal levels of sugar or protein.



CT Scan

CT (computed tomography) scanning is a technique in which multiple X-rays of thebody are taken from different angles in a very short period of time. These images

are then fed into a computer, which creates a series of images that look like "slices"through the body. CT scans can show certain changes that are characteristic ofAlzheimer's disease in its later stages. These changes include a reduction in thesize of the brain, referred to as atrophy.

Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging, usually called MRI, is a test that produces very clearpictures, or images, of the human body without using X-rays. Instead, MRI uses alarge magnet, radio waves, and a computer to produce these images. MRI isbeneficial in ruling out other causes of dementia, such as tumors or strokes. It alsomay help to show the structural and functional changes in the brain that areassociated with Alzheimer's disease.

Electroencephalography (EEG)

Electroencephalography (EEG) is a medical technique that measures brain function

by analyzing the electrical activity generated by the brain. This activity is measuredthrough special electrodes applied to the scalp. EEG can be contributing to



Electrocardiogram (ECG)

An electrocardiogram (ECG) is a recording of the heart's electrical activity. Thisactivity is registered as a graph or series of wavy lines on a moving strip of

paper. This gives the doctor important information about the heart. This test maybe used by the doctor to help rule out other conditions that may be causingsymptoms similar to those of Alzheimer's disease.

Single Photon Emission Computed Tomography (SPECT) Scan

SPECT is a technique for creating very clear, three-dimensional pictures of amajor organ, such as the brain or heart. SPECT scans involve the injection of avery small amount of a radioactive substance. Energy from the radioactivesubstance in the body is detected by a special camera, which then takes thepictures.

Positron Emission Tomography (PET) Scan

PET scanning is a three-dimensional imaging technique that allows a doctor toexamine the heart, brain, or other internal organs. PET scans also can showhow the organs are functioning. PET scans can show the difference in brain

activity between a normal brain and one affected by Alzheimer's disease; it canalso help differentiate Alzheimer's disease from other forms of dementia.



PET scan of normal brain PET scan of Alzheimer’s

disease brain



CAN BLOOD TEST DIAGNOSE

ALZHEIMER’S………???

A new blood test for Alzheimer's disease is 96% accurateat identifying the disease and can perhaps detect it evenbefore symptoms such as memory loss appear, says thetest's developer.

''This is a simple test that has high accuracy and can berun from a single drop of blood," says Robert Nagele,founder of Durin Technologies Inc., the company that isdeveloping the test

The research results on the new test are published onlinein PLoS ONE.



HOW IT WORKS…….

Nagele's test looks for antibodies in the blood specific to the disease.Alzheimer's is believed to start up to 10 years or so before symptoms arenoticeable.

Brain cells die and when they die, they pop, they explode, like a water

balloon breaking.The contents of those dying cells spill partially back into the blood.

Body makes antibodies against the cell debris that happens to facilitate thecleanup of the cell debris.

Nagele's team looked at blood samples from 50 people with Alzheimer'sdisease and 40 without Overall, the tests identified 96% of those withAlzheimer's correctly. It correctly identified 92.5% of those who didn't haveAlzheimer's.



Testing urine means testing something that has alreadybroken down in the body.

Cerebral spinal fluid tests require an invasive spinal tap.

Blood is always the method of choice

THEY ARE PREFERRING BLOOD

TEST DUE TO THE FOLLOWING

THREE REASONS……………



TREATMENT

There is no cure for Alzheimer's disease and no treatment to reverse or halt its

progression.

Health care providers may use medicines to help manage troubling symptoms ofAlzheimer's disease, including depression, behavioral problems etc.

Doctor will determine the best treatment for the Alzheimer’s patient based on

various factors, including:

The patient’s age, overall health, and medical history Extent of the disease

The patient’s tolerance for specific medicines and therapies



DRUGS USED TO TREAT

ALZHEIMER’S

Cholinesterase inhibitors (Aricept, Cognex, Exelon, Razadyne)

Cholinesterase inhibitors curb the breakdown of acetylcholine, a chemical in thebrain important for memory and learning. These drugs may slow the progression ofsymptoms for about half of people taking them for a limited time, on average 6 to

12 months.

Aricept is the only treatment approved by the FDA for all stages of Alzheimer’s

disease: mild, moderate, and severe. It is available as tablets to swallow or tabletsto dissolve in the mouth.

Cognex was the first of these drugs to be FDA approved, but it is used lesscommonly than the other medications.

Exelon is approved for use in mild to moderate Alzheimer’s dementia and is

available as a skin patch, capsules, and liquid form.

Razadyne (formerly Reminyl) is also approved for mild to moderate Alzheimer’s



Common side effects include diarrhea, vomiting, nausea, fatigue,insomnia, loss of appetite, and weight loss.

Namenda

it is thought to play a protective role in the brain by regulating the activityof a brain chemical called glutamate.

Glutamate plays a role in learning and memory.

Brain cells in people with Alzheimer’s disease release too much

glutamate.

Namenda is the only drug for Alzheimer’s that works this way. It mayimprove mental function and performance of daily activities for somepeople.

Side effects of Namenda include tiredness, dizziness, confusion,constipation, and headache



USING SURGERY……

There is no surgical treatment for Alzheimer's disease at this time.

USING GENE THERAPY……

A new gene therapy that was successful in treating memory problems inmice with Alzheimer’s disease (AD)was discovered by scientists.

EphB2 is a molecule that acts as both a receptor and an enzyme. It is

thought to be involved in memory problems of AD because it is a masterregulator of neurotransmission and its brain levels are decreased in thedisease.

Reducing EphB2 levels in normal healthy mice disrupted neurotransmission

and gave them memory problems similar to those seen in AD.

The researchers conclude that depletion of EphB2 is important in ―amyloid-b-induced neuronal dysfunction‖ and that increasing EphB2 levels or

function could be beneficial in Alzheimer’s disease



The findings, published, in Human Molecular Genetics suggests injecting extraparkin genes could clear the brain of the amyloid particles.

In the current study, the researchers showed the parkin gene degrades the amyloid

beta protein.

A mouse model mimicing the early stages of Alzheimer's disease was delivered aninactive HIV lentivirus into the motor cortex of the mouse brains. It caused amyloidplaque to form inside the neurons, but not outside the cells. The hypothesis is thatonce amyloid builds inside the cells, the neurons burst leading to amyloid proteinclumping and plaque between the brain cells.

Injected with the parkin protein on one side of the brain, leaving the otheruntouched as a control.

The team found the boosting the parkin gene cleared the brain of Alzheimer'sproducing plaque.

In the study, the parkin gene cleared away enough amyloid beta plaque in the brainthat the researchers say regaining memory might be possible even after damagehas occurred.



USING STEM CELL…..

In the study, published in the journal Stem Cells, researchers describe anew method of duplicating the neurons using human embryonic stemcells.

They transplanted the new cells into the brains of mice .

The results showed that the cells, known as basal forebrain cholinergicneurons, developed which help the hippocampus retrieve memories inthe brain, an ability that is lost in early Alzheimer’s disease.

Once there, these cells formed new connections with the surroundingcells and began producing acetylcholine, just like normal brain cells.



SURVIVAL RATE

Once the onset of Alzheimer's has begun it will be present in thevictim's life until he dies.

Alzheimer's patients may die from infections they obtain in the latestages of the disease.

People with Alzheimer's disease often live for years with the disease.

The duration of Alzheimer's disease from time of diagnosis can be 20

years or more.

The average length of time from onset of symptoms is thought to be inthe range of 4 to 8 years.



ORGANISATIONS

Alzheimer’s and Related disorders Society Of India (ARDSI) , Cochin ,

Kerala

Memory Clinic at Asha Hospital, Hyderabad, Andhra Pradesh, India.

Agrawal Hospital in Vasai. India, 2011.

First such centre in the State, the two-storey Agarwal Hospital will takecare of 250 patients at the cost of Rs 500 per day per patient

ICRI (Institute Of Clinical Research ) , India

Trust Hospital in New Delhi, India ( Alzheimer's Stem Cell Therapy isavailable)

Alzheimer's Association , United States of America



THANK

YOU

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Alzheimer's - GN0453

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