Alzheimer's Disease Flashcards

1
Q

Neurodegenerative disease

A

• a condition which affects brain function, and results from deterioration of neurons.
• They are divided into 2 groups:
– dementia
– affecting movements

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2
Q

Neurodegenerative disease examples

A
– Examples:
Alzheimer’s
Parkinson’s
Huntington’s
Creutzfeldt-Jakob disease
Multiple Sclerosis
Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease)
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3
Q

Neurodegenerative Diseases risk factorrs

A

Known

  • Certain genetic polymorphisms
  • Increasing age

Possible

  • Gender
  • Poor education
  • Endocrine conditions
  • Oxidative stress
  • Inflammation
  • Stroke
  • Hypertension
  • Diabetes
  • Head trauma
  • Depression
  • Infection
  • Tumors
  • Vitamin deficiencies
  • Immune and metabolic conditions
  • Chemical exposure
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4
Q

Neurodegenerative Diseases protective factors

A
  • Estrogen
  • SIRT1 (sirtuin1) protein
  • Smoking
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5
Q

Mitotic vs Post-Mitotic cells

A

Mitotic cells are capable of proliferation;
Include the epithelial, stromal (fibroblastic) and vascular (endothelial) cells that comprise the major renewable tissues and organs such as the skin, intestines, liver, kidney, etc.
Also major components of the haematopoietic system, and glial cells;
Also undifferentiated stem and progenitor cells;

Post-mitotic cells are incapable of proliferation;
Include the nondividing neurons and muscle cells that comprise the brain, heart and skeletal muscle;
Post-mitotic cells can undergo limited repair and regeneration;
however, this regeneration is not due to the proliferation of
post-mitotic cells, but rather to the recruitment of mitotic stem cells or their progeny (progenitor cells).

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6
Q

Historical and Current Dogma of the Ageing Brain

A

Historical perspective
• Accelerated rate of brain shrinkage after age 50.
• Loss of 100,000 neurons in the cortex per day.
• Irreversible process of brain dysfunction.

Current perspective
•Insignificant loss of neurons.
• Loss of synaptic connections.
• Evidence of brain plasticity.

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7
Q

Dementia

A

A progressive reduction of cognitive function, leading to a serious loss of global cognitive ability;
Occurring at all ages but most frequent over age 75,
beyond what might be expected from normal ageing; >4% of people over 65 exhibit dementia;
Is not a single disease, but a non-specific illness syndrome. (affecting memory, attention, language, problem solving, generally in the area of cerebral cortex).
Symptoms present > 6 months to support a diagnosis

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8
Q

Alzheimer’s Disease

A

Memory loss, personality changes, global cognitive dysfunction; Visual spatial, language disturbances;
Delusions/hallucinations (usually later in course) in 1/3
Depression occurs in 1/3

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9
Q

Alzheimer’s Disease (AD)

A

• Familial AD (onset < 60 y/o) (<5%)
– Presenilin I, II (ch 14, 1)
– APP (ch 21)
• Non-familial (late onset)
APOE (40 – 50% due to e4)
 Apolipoprotein E (APOE) found on chromosome 19.
 APOE comes in several different forms, or alleles.
Three forms—APOE ε2, APOE ε3, and APOE ε4
 APOE helps carry cholesterol in the bloodstream.
 APOE also transports A-beta
• Environmental factors
– Susceptible: Head trauma, stroke, Total cholesterol,
stress, Hypertension;
– Protectable: N.S.A.I.D.’s, Estrogen, Education

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10
Q

Beta-amyloid Plaques

A

Amyloid precursor protein (APP) is the precursor to amyloid plaque.
1. APP sticks through the neuron membrane.
2. Enzymes cut the APP into fragments of protein, including beta-amyloid.
3. Beta-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

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11
Q

Neurofibrillary tangle

A

In AD tau protein is hyperphosphorylated, defective and detaches from the microtubules;
Connections between neurones are lost;
Defective tau proteins then assemble to form filaments in
the neuron and create neurofibrillary tangles;
Loss of axonal transport results in cell death

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12
Q

AD Progress Stages

A
Mild symptoms: 
•Memory loss
•Language problems
•Mood swings
•Personality changes
•Diminished judgment
Moderate symptoms:
•Behavioural, personality changes
•Unable to learn/recall new information
•Long-term memory affected
•Wandering, agitation, aggression, confusion
•Require assistance
Severe symptoms:
•Gait, incontinence, motor disturbances
•Bedridden
•Unable to perform ADL (activities of daily living)
•LTC (long term care) placement needed
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13
Q

NT imbalance in AD

A

• Acetylcholine
– levels of acetylcholine in AD brain are abnormally low
– the loss of cholinergic neurons in hippocampus and
frontal cortex is the feature of the disease
– loss of ACh in AD correlates with impairment of memory
– loss of ACh contributes to cognitive decline in AD
– It may contribute to behavioral symptoms of AD
– psychosis-agitation; Apathy-indifference;
– disinhibition; Aberrant motor behavior
• Glutamate
– Levels of the excitatory neurotransmitter, glutamate,
are elevated

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14
Q

CURRENT THERAPY for AD

A
  • SSRI
  • theino
  • Benzodiazepines
  • Dppamine antagonist
  • Reversible
    Acetylcholinesterase
    Inhibitor
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15
Q

Acetylcholinesterase Inhibitor - Development

A

• 1st Generation
Tacrine hepatotoxic, not on use, last choice
• 2nd Generation
Donepezil (Aricept®)
Rivastigmine (Exelon®)
Galantamine (Razadyne®) formerly known as (Reminyl®)

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16
Q

Aricept® (Donepezil)

A
  • The most widely used drug for AD.
  • the only treatment approved by the FDA for all stages of AD.
  • 100% bioavailability.
  • Can cross the blood-brain barrier
17
Q

Exelon® (Rivastigmine)

A

Rivastigmine is a cholinesterase inhibitor that inhibits both butyrylcholinesterase and acetylcholinesterase.
When given orally, bioavailability is about 40% in the 3 mg dose.
The compound can cross the blood-brain barrier

18
Q

Razadyne® (Galantamine)

A

It is well absorbed with absolute oral bioavailability between 80 and 100%. It has a half-life of 7 hours;
It has not shown to alter the underlying dementia process

19
Q

Namenda® (Memantine)

A

Acting on the glutamatergic system by blocking NMDA glutamate receptors.
Blocks the toxic effects associated with excess glutamate and regulates glutamate activation

20
Q

Summary of Alzheimer’s disease drugs

A

Slide 24

21
Q

Current management of AD

A

• Improving mental functioning
– Mild to Moderate AD: cholinesterase inhibitors delay or prevent symptoms getting worse for a limited time and control some behavioral symptoms
– Moderate to Severe AD: NMDA antagonist delay progression to severe AD; allow patients to maintain certain daily functions a little longer
• Management of confusion and agitation (avoid the
chronic use of sedatives, psychoactives agents; betablocking agents and anticholinergics)
• Risk factor reduction: e.g. control of vascular risk factors, especially hypertension;
• Maintaining patient at home;
• Social supports more valuable than medications

22
Q

Alzheimer’s: The Race to Cure

A

• Vaccination: Anti Ab immunotherapy reduces amyloid
deposition and improved spatial cognition in mice
• Clinical trial in 298 patients with AD:18 developed
inflammatory meningoencephalitis: study halted
• Autopsy in one: “less amyloid than expected”
• In subgroup of 30 patients, those who generated Ab
antibodies had reduced disease progression
• Attempts being made to reformulate vaccine
• Passive immunization considered

23
Q

Summary

A

• AD is a degenerative, progressive, terminal disease that slowly destroys memory and think skills;
• AD is not a part of normal ageing.
• It is caused by a fatal disease that affects the brain;
• There are two microscopic features: senile plaques and neurofibrillary tangles;
• Current drug treatment:
Acetylcholinesterase inhibitors
NMDA antagonists;
• No cure yet

24
Q

Common diseases leading to dementia

A
  1. Alzheimer Disease (pure ~40%, + mixed~70%)
  2. Vascular Disease, MID (5-20%)
  3. Drugs interaction, Ethanol (5-15%)