Alzheimer's Disease Flashcards
Neurodegenerative disease
• a condition which affects brain function, and results from deterioration of neurons.
• They are divided into 2 groups:
– dementia
– affecting movements
Neurodegenerative disease examples
– Examples: Alzheimer’s Parkinson’s Huntington’s Creutzfeldt-Jakob disease Multiple Sclerosis Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease)
Neurodegenerative Diseases risk factorrs
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
Neurodegenerative Diseases protective factors
- Estrogen
- SIRT1 (sirtuin1) protein
- Smoking
Mitotic vs Post-Mitotic cells
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).
Historical and Current Dogma of the Ageing Brain
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.
Dementia
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
Alzheimer’s Disease
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
Alzheimer’s Disease (AD)
• 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
Beta-amyloid Plaques
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
Neurofibrillary tangle
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
AD Progress Stages
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
NT imbalance in AD
• 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
CURRENT THERAPY for AD
- SSRI
- theino
- Benzodiazepines
- Dppamine antagonist
- Reversible
Acetylcholinesterase
Inhibitor
Acetylcholinesterase Inhibitor - Development
• 1st Generation
Tacrine hepatotoxic, not on use, last choice
• 2nd Generation
Donepezil (Aricept®)
Rivastigmine (Exelon®)
Galantamine (Razadyne®) formerly known as (Reminyl®)
