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ALZHEIMER’S DISEASE
DEFINITION:
Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by
cognitive & behavioural impairment that significantly interferes with social &
occupational functioning.
Alzheimer’s disease is also known as senile dementia of the Alzheimer type
(SDAT) or simply Alzheimer’s, the most common form of dementia. It is an incurable,
degenerative, terminal disease.
AD results from an increase in the production or accumulation of specific protein
(β-amyloid protein) in the brain that leads to nerve cell death.
EPIDEMIOLOGY
:
According to 2015 report, AD affects 5.3 million people in US.
AD was the 6th leading cause of death in 2015.
AD and other dementias are more likely common in African Americans, than in
whites.
According to the WHO’s review in 2000, on the “global burden of dementia”:
approximate rates of dementia are under 1% in persons aged 60-69 years and 39%
in persons aged 90-95 years, prevalence doubles with every 5 years of age (within
the above ranges).
ETIOLOGY:
The exact etiology of Alzheimer’s disease is not known and associated with risk
factors. But stated that there are several genetical and environmental factors have
been explored as potential causes of the Alzheimer’s disease.
Other factors include:
1. Advancing age
2. Family history
3. Trauma
4. Education
5. Vascular disease like stroke etc.
RISK FACTORS:
The common risk factors for
developing Alzheimer’s disease are:
Increased age (over 65 years of age)
Hypertension (high blood pressure)
Increased cholesterol levels
Coronary artery disease
Diabetes
Other risk factors are:
Genetics
Smoking and alcohol use
Plasma homocysteine
Down syndrome
Mild cognitive impairment
P
ATHOPHYSIOLOGY:
The brain has billions of neurons, each with an axon and many dendrites. To stay
healthy, neurons must communicate with each other, carry out metabolism and
repair themselves. AD disrupts all three of these essential jobs.
There are two signature lesions in Alzheimer’s disease. They are:
1. Neuritic plaques/ β-amyloid plaques, which are dense deposits of protein and
cellular material that accumulate outside and around nerve cells.
2. Neurofibrillary tangles (NFT’s), which are twisted fibers that build up inside the
nerve cell.
1
. NEURITIC PLAQ
UES:
Deposits of a protein fragment called β-amyloid, that accumulates in the spaces
between the nerve cells (neurons).
APP (amyloid precursor protein) is the precursor of amyloid plaque.
a) APP sticks through the neuron membrane.
b) Enzymes like β-secretase and α-secretase cut the APP into fragments of protein
(neurotoxic Aβ42 fragment), including β-amyloid.
c) β-amyloid fragments come together in clumps to form plaques.
In AD, many of these clumps form, disrupting the work of neurons. This affects the
hippocampus and other areas of the cerebral cortex.
APP (amyloid precursor protein)
Cleaved by β-secretase and α-secretase
M utation of amyloid precursor protein on chromosome no. 21
Increased production of amyloid precursor protein
Produces of amyloid protein
Accumulation of β-amyloid protein
(due to increased production of APP)
Directly neurotoxin
Alzheimer’s disease
2
. NEUROFIBRILLAR
Y T
ANGLES (NFT’S):
Neurons have an internal support structure
partly made up of microtubules. A protein called
“tau” helps to stabilize microtubules. In AD, “tau”
changes, causing microtubules to collapse and
“tau” proteins clump together to form
neurofibrillary tangles.
CONTD…
Although autopsy studies show that most people develop
some plaques & tangles as they age
Those with AD tend to develop them far more & in a predictable pattern
They develop in the areas important for memory
before spreading to other regions
Plaques & tangles disable/block communication among neurons
G radually spread to other areas of brain
Causes symptoms of Alzheimer’s disease
SYMPTOMS:
The symptoms of AD are classified as:
1. Cognitive symptoms
2. Non cognitive symptoms
3. Functional symptoms
CONTD…
1. Cognitive symptoms:
 Memory loss (poor recall and losing
items)
 Aphasia (circumlocution and anomia)
 Apraxia, agnosia,
 Disorientation (impaired perception of
time and unable to recognize familiar
people)
 Impaired executive function.
2. Non cognitive symptoms:
 Depression, psychotic
(hallucination and delusions).
symptoms
 Behavioural disturbances (physical and
verbal aggression, motor hyperactivity,
uncooperativeness, wandering, repetitive
mannerisms and activities and
combativeness).
3. Functional symptoms:
 Inability to care for self (dressing, bathing,
eating etc.)
CLINICAL MANIFEST
ATIONS/ST
AGES OF
ALZHEIMER’S DISEASE (AD):
AD can be divided into 5 stages:
1. Pre-clinical AD
2. Mild AD
3. Moderate AD
4. Severe AD
5. End-stage AD
CONTD…
 1. Pre-clinical AD:
 Patient may appear normal on physical examination & mental status testing.
 Specific regions of brain (entorhinal cortex, hippocampus) are likely to be
affected, decades before ant signs/symptoms appear.
 2. M ild AD: Sig ns include:
 Memory loss, confusion about location of familiar places, taking longer
time to accomplish normal, daily tasks (trouble in handling money & paying
bills).
 Compromised judgement, often leading to bad decisions.
 Loss of spontaneity & sense of initiative.
 Mood & personality changes (increased anxiety).
CONTD…
3. M oderate AD: Signs include:
 Increased memory loss, increased confusion, shortened attention span.
 Problems recognizing friends & family members, difficulty in language, problems
with reading, writing, working with numbers.
 Difficulty organizing thoughts and in logical thinking.
 Inability to learn new things/to cope with new/unexpected situations.
 Restlessness, agitation, anxiety, tearfulness, hallucinations, delusions, irritability.
 Loss of impulse control.
 Perceptual-motor problems (e.g. trouble getting out of a chair/setting the table).
CONTD…
 4. Severe AD: Sig ns include:
 Patient with severe AD can’t recognize the family/loved ones.
 Can’t communicate effectively, completely depend on others for care.
 All sense of self seems to vanish.
 Other symptoms include weight loss, seizures, skin infections, dysphagia,
groaning,
 moaning/grunting, increased sleeping lack of bladder & bowel control.
 5. End-stage AD:
 During end-stage AD, patients are in bed all of the time.
 Death usually occurs doe to other illness, notably aspiration pneumonia.
DIAGNOSIS:
These include;
1. Blood studies
2. Brain MRI/CT-scan
3. SPEC T (Single Positron Emission C omputerized Tomography)/PET (Positron
Emission Tomography)
4. Lumbar puncture
5. Genotyping
6. Electroencephalography
MANAGEMENT OF AD:
Goals of therapy:
1. To maintain patient’s brain function as far as possible.
2. To treat patient’s psychiatric and behaviour sequelae.
3. To decelerate the likelihood of progression into complications.
4. To focus on emotional & supportive care for the concerned patient.
5. To reduce morbidity & mortality as far as possible.
6. To improve quality of life.
PHARMACOLOGICAL TREA
TMENT:
1. Cholinesterase inhibitors:
MOA:
These drugs selectively inhibit acetyl cholinesterase, the enzyme responsible for
the destruction of acetyl choline. Thus, acetyl choline gets accumulated (improves
Ach availability) and produces cholinergic effects.
Acetyl CoA + Choline
Choline acetyl transferase
Acetyl choline (Ach)
Acetyl cholinesterase
C holine + Acetate
Cholinesterase inhibitors
(e.g. donepezil, rivastigmine, galantamine)
CONTD…
ADRs: Adverse effects of anticholinesterases include increased sweating, salivation,
nausea, vomiting, abdominal cramps, bradycardia, diarrhea, tremors and
hypertension.
Uses: They are mainly used in the treatment of Alzheimer’s disease, myasthenia
gravis, belladonna poisoning, curare poisoning, post-operative urinary retention and
paralytic ileus.
Dose:
 Donepezil: 5-10mg OD (for mild-moderate AD), 10-20mg (for moderate-severe AD)
 Rivastigmine: 1.5mg PO, BD (initial dose), 12mg/day PO (Max. dose)
 Galantamine: 16-24 mg/day (maintenance dose)
CONTD…
2. NM DA receptor antagonists (M emantine):
MOA:
The N-methyl-D-aspartate receptor (also known as NMDA receptor) is a glutamate
receptor and ion channel protein found in nerve cells. The NMDA receptor is very
important in controlling synaptic plasticity and memory function. NMDA type
glutamate receptors may be over activated in AD (glutamatergic excitotoxicity).
Memantine binds preferentially to NMDA receptor and blocks it. Blocking usually
occurs only under conditions of excessive stimulation and not under
neurotransmission.
C
O
NTD…
Memantine
Blocks
NMDA receptor (blocks glutamate)
Prevents too much calcium from moving into the brain cells
Reduces excessive stimulation
Reduces the symptoms of Alzheimer’s disease
 ADRs: Hypertension, cataract, CVA, thromboembolism etc.
 Uses: It is commonly used for moderate-severe dementia in patients with AD.
 Dose: Memantine: 5mg OD (initial dose); 20mg/day (Max. dose)
Patient diagnosed with AD according to NINCDS-ADRDA criteria
Assess all comorbid medical disorders and drug therapies that
may affect cognition
Rule out comorbid depression
Evaluate for pharmacotherapy based on illness stage
Moderate-severe AD
Cholinesterase inhibitor, memantine or
combination of cholinesterase inhibitor
and memantine
+
Vitamin E
Mild AD
Cholinesterase inhibitor or memantine
+
Vitamin E
Stable MMSE
(<4-point decline over 1 year)
Continue regimen above
Deteriorating MMSE
(≥4-point decline over 1 year)
Alternate from above + vitamin E
Treatment algorithm for Alzheimer’s disease
Presentation for Alzheimers Disease.pptx

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Presentation for Alzheimers Disease.pptx

  • 2. DEFINITION: Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by cognitive & behavioural impairment that significantly interferes with social & occupational functioning. Alzheimer’s disease is also known as senile dementia of the Alzheimer type (SDAT) or simply Alzheimer’s, the most common form of dementia. It is an incurable, degenerative, terminal disease. AD results from an increase in the production or accumulation of specific protein (β-amyloid protein) in the brain that leads to nerve cell death.
  • 3. EPIDEMIOLOGY : According to 2015 report, AD affects 5.3 million people in US. AD was the 6th leading cause of death in 2015. AD and other dementias are more likely common in African Americans, than in whites. According to the WHO’s review in 2000, on the “global burden of dementia”: approximate rates of dementia are under 1% in persons aged 60-69 years and 39% in persons aged 90-95 years, prevalence doubles with every 5 years of age (within the above ranges).
  • 4. ETIOLOGY: The exact etiology of Alzheimer’s disease is not known and associated with risk factors. But stated that there are several genetical and environmental factors have been explored as potential causes of the Alzheimer’s disease. Other factors include: 1. Advancing age 2. Family history 3. Trauma 4. Education 5. Vascular disease like stroke etc.
  • 5. RISK FACTORS: The common risk factors for developing Alzheimer’s disease are: Increased age (over 65 years of age) Hypertension (high blood pressure) Increased cholesterol levels Coronary artery disease Diabetes Other risk factors are: Genetics Smoking and alcohol use Plasma homocysteine Down syndrome Mild cognitive impairment
  • 6. P ATHOPHYSIOLOGY: The brain has billions of neurons, each with an axon and many dendrites. To stay healthy, neurons must communicate with each other, carry out metabolism and repair themselves. AD disrupts all three of these essential jobs. There are two signature lesions in Alzheimer’s disease. They are: 1. Neuritic plaques/ β-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells. 2. Neurofibrillary tangles (NFT’s), which are twisted fibers that build up inside the nerve cell.
  • 7. 1 . NEURITIC PLAQ UES: Deposits of a protein fragment called β-amyloid, that accumulates in the spaces between the nerve cells (neurons). APP (amyloid precursor protein) is the precursor of amyloid plaque. a) APP sticks through the neuron membrane. b) Enzymes like β-secretase and α-secretase cut the APP into fragments of protein (neurotoxic Aβ42 fragment), including β-amyloid. c) β-amyloid fragments come together in clumps to form plaques. In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex.
  • 8. APP (amyloid precursor protein) Cleaved by β-secretase and α-secretase M utation of amyloid precursor protein on chromosome no. 21 Increased production of amyloid precursor protein Produces of amyloid protein Accumulation of β-amyloid protein (due to increased production of APP) Directly neurotoxin Alzheimer’s disease
  • 9. 2 . NEUROFIBRILLAR Y T ANGLES (NFT’S): Neurons have an internal support structure partly made up of microtubules. A protein called “tau” helps to stabilize microtubules. In AD, “tau” changes, causing microtubules to collapse and “tau” proteins clump together to form neurofibrillary tangles.
  • 10. CONTD… Although autopsy studies show that most people develop some plaques & tangles as they age Those with AD tend to develop them far more & in a predictable pattern They develop in the areas important for memory before spreading to other regions Plaques & tangles disable/block communication among neurons G radually spread to other areas of brain Causes symptoms of Alzheimer’s disease
  • 11. SYMPTOMS: The symptoms of AD are classified as: 1. Cognitive symptoms 2. Non cognitive symptoms 3. Functional symptoms
  • 12. CONTD… 1. Cognitive symptoms:  Memory loss (poor recall and losing items)  Aphasia (circumlocution and anomia)  Apraxia, agnosia,  Disorientation (impaired perception of time and unable to recognize familiar people)  Impaired executive function. 2. Non cognitive symptoms:  Depression, psychotic (hallucination and delusions). symptoms  Behavioural disturbances (physical and verbal aggression, motor hyperactivity, uncooperativeness, wandering, repetitive mannerisms and activities and combativeness). 3. Functional symptoms:  Inability to care for self (dressing, bathing, eating etc.)
  • 13. CLINICAL MANIFEST ATIONS/ST AGES OF ALZHEIMER’S DISEASE (AD): AD can be divided into 5 stages: 1. Pre-clinical AD 2. Mild AD 3. Moderate AD 4. Severe AD 5. End-stage AD
  • 14. CONTD…  1. Pre-clinical AD:  Patient may appear normal on physical examination & mental status testing.  Specific regions of brain (entorhinal cortex, hippocampus) are likely to be affected, decades before ant signs/symptoms appear.  2. M ild AD: Sig ns include:  Memory loss, confusion about location of familiar places, taking longer time to accomplish normal, daily tasks (trouble in handling money & paying bills).  Compromised judgement, often leading to bad decisions.  Loss of spontaneity & sense of initiative.  Mood & personality changes (increased anxiety).
  • 15. CONTD… 3. M oderate AD: Signs include:  Increased memory loss, increased confusion, shortened attention span.  Problems recognizing friends & family members, difficulty in language, problems with reading, writing, working with numbers.  Difficulty organizing thoughts and in logical thinking.  Inability to learn new things/to cope with new/unexpected situations.  Restlessness, agitation, anxiety, tearfulness, hallucinations, delusions, irritability.  Loss of impulse control.  Perceptual-motor problems (e.g. trouble getting out of a chair/setting the table).
  • 16. CONTD…  4. Severe AD: Sig ns include:  Patient with severe AD can’t recognize the family/loved ones.  Can’t communicate effectively, completely depend on others for care.  All sense of self seems to vanish.  Other symptoms include weight loss, seizures, skin infections, dysphagia, groaning,  moaning/grunting, increased sleeping lack of bladder & bowel control.  5. End-stage AD:  During end-stage AD, patients are in bed all of the time.  Death usually occurs doe to other illness, notably aspiration pneumonia.
  • 17. DIAGNOSIS: These include; 1. Blood studies 2. Brain MRI/CT-scan 3. SPEC T (Single Positron Emission C omputerized Tomography)/PET (Positron Emission Tomography) 4. Lumbar puncture 5. Genotyping 6. Electroencephalography
  • 18. MANAGEMENT OF AD: Goals of therapy: 1. To maintain patient’s brain function as far as possible. 2. To treat patient’s psychiatric and behaviour sequelae. 3. To decelerate the likelihood of progression into complications. 4. To focus on emotional & supportive care for the concerned patient. 5. To reduce morbidity & mortality as far as possible. 6. To improve quality of life.
  • 19. PHARMACOLOGICAL TREA TMENT: 1. Cholinesterase inhibitors: MOA: These drugs selectively inhibit acetyl cholinesterase, the enzyme responsible for the destruction of acetyl choline. Thus, acetyl choline gets accumulated (improves Ach availability) and produces cholinergic effects. Acetyl CoA + Choline Choline acetyl transferase Acetyl choline (Ach) Acetyl cholinesterase C holine + Acetate Cholinesterase inhibitors (e.g. donepezil, rivastigmine, galantamine)
  • 20. CONTD… ADRs: Adverse effects of anticholinesterases include increased sweating, salivation, nausea, vomiting, abdominal cramps, bradycardia, diarrhea, tremors and hypertension. Uses: They are mainly used in the treatment of Alzheimer’s disease, myasthenia gravis, belladonna poisoning, curare poisoning, post-operative urinary retention and paralytic ileus. Dose:  Donepezil: 5-10mg OD (for mild-moderate AD), 10-20mg (for moderate-severe AD)  Rivastigmine: 1.5mg PO, BD (initial dose), 12mg/day PO (Max. dose)  Galantamine: 16-24 mg/day (maintenance dose)
  • 21. CONTD… 2. NM DA receptor antagonists (M emantine): MOA: The N-methyl-D-aspartate receptor (also known as NMDA receptor) is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is very important in controlling synaptic plasticity and memory function. NMDA type glutamate receptors may be over activated in AD (glutamatergic excitotoxicity). Memantine binds preferentially to NMDA receptor and blocks it. Blocking usually occurs only under conditions of excessive stimulation and not under neurotransmission.
  • 22. C O NTD… Memantine Blocks NMDA receptor (blocks glutamate) Prevents too much calcium from moving into the brain cells Reduces excessive stimulation Reduces the symptoms of Alzheimer’s disease  ADRs: Hypertension, cataract, CVA, thromboembolism etc.  Uses: It is commonly used for moderate-severe dementia in patients with AD.  Dose: Memantine: 5mg OD (initial dose); 20mg/day (Max. dose)
  • 23. Patient diagnosed with AD according to NINCDS-ADRDA criteria Assess all comorbid medical disorders and drug therapies that may affect cognition Rule out comorbid depression Evaluate for pharmacotherapy based on illness stage Moderate-severe AD Cholinesterase inhibitor, memantine or combination of cholinesterase inhibitor and memantine + Vitamin E Mild AD Cholinesterase inhibitor or memantine + Vitamin E Stable MMSE (<4-point decline over 1 year) Continue regimen above Deteriorating MMSE (≥4-point decline over 1 year) Alternate from above + vitamin E Treatment algorithm for Alzheimer’s disease