lecture 10 Flashcards
(57 cards)
Alzheimer’s disease
It is the most common cause of dementia among older people (> 60).
Progressive short-term memory failure, impaired ability to think and concentrate, inability to reason normally or to learn new information, and confusion or disorientation to such an extent that it interferes with a person’s daily life and activities.
It is not a normal part of aging. Affects all aspects of life (cognitive, emotional, behavior, physical)
There may be changes in personality, speech disturbances, restlessness, and inability to perform normal tasks of daily living.
Once advanced, the disease causes the patient to be emotionally detached, and often, hostile to others.
Mild Alzheimer’s Disease
Memory loss worsens, and
Changes in other cognitive abilities are evident. (for example, getting lost, trouble handling money and paying bills, repeating questions, taking longer to complete normal daily tasks, using poor judgment, and having some mood and personality changes.)
People often are DIAGNOSED in this stage.
Moderate Alzheimer’s Disease
Damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought.
Memory loss and confusion grow worse,
They begin to have problems recognizing family and friends.
They may be unable to learn new things, carry out tasks that involve multiple steps (such as getting dressed), or cope with new situations. They may have hallucinations, delusions, and paranoia, and may behave impulsively.
Severe Alzheimer’s Disease
PLAQUES and TANGLES have SPREAD throughout the brain, and brain tissue has shrunk significantly.
People with severe Alzheimer’s cannot communicate and are completely dependent on others for their care.
The person may be in bed most or all of the time as the body shuts down.
(SEE IMAGE)
Plaques
THESE CLUMPS OF A PROTEIN CALLED BETA-AMYLOID may damage and destroy brain cells in several ways, including interfering with cell-to-cell communication.
Although the ultimate cause of brain-cell death in Alzheimer’s isn’t known, abnormal processing of beta-amyloid is a prime suspect.
*On the outside of neurons
Tangles
Brain cells depend on an internal support and transport system to carry nutrients and other essential materials throughout their long extensions.
This system requires the normal structure and functioning of a protein called tau.
In Alzheimer’s, THREADS OF TAU PROTEIN TWIST INTO ABNORMAL TANGLES, leading to failure of the transport system.
This failure is also strongly implicated in the decline and death of brain cells.
*On inside of nerve cells (fibers inside neurons that get tangled)
Mechanism – APO Isoforms
No specific gene directly causes the late-onset form of the disease.
However, one GENETIC risk factor—having one form of the APOLIPOPROTEIN E (APOE) GENE ON CHROMOSOME 19 —does increase a person’s RISK
APOE comes in several different forms, or alleles:
APOE ɛ2
Relatively rare and MAY PROVIDE SOME PROTECTION against the disease.
- If Alzheimer’s disease occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE ɛ4 gene.
*We want this, it is protective!
APOE ɛ3
The most common allele,
is believed to PLAY A NEUTRAL ROLE play a neutral role in the disease— neither decreasing nor increasing risk.
APOE ɛ4
INCREASES RISK FOR ALZHEIMER’S disease and is also associated with an EARLIER age of disease onset.
- A person has zero, one, or two APOE ɛ4 alleles.
- Having more APOE ɛ4 alleles increases the risk of developing Alzheimer’s
*You can have different combinations of these to increase or decrease your risk because you get them from both parents (eg. you could have a 3 and a 4)
APOE 4 gain and loss of function
Outside the brain, APOE4 can increase the risk of atherosclerosis and stroke, which may explain why APOE4 is a risk factor for vascular causes of cognitive impairment and dementia.
Inside the brain, APOE helps to CLEAR BETA-AMYLOID, a component of plaques.
APOE2 appears to perform this function more effectively than APOE4
*The things you gain are negative, the things you lose were good things (get a feel for these kinds of things rather than forcing the information)
(SEE IMAGE)
APOE distribution and risk of disease
Only 5% of the population have 2 copies of 4 (the bad one)
(SEE IMAGE)
APO e isoforms
SEE IMAGE FOR THE DIFFERENCES
- clearance of amyloid requires ApoE (good one)
*Changes in the sequence
*2 is cysteine at ….
*4 has arginine at …
Alzheimer’s Disease
In the brain of a person with Alzheimer’s disease, THERE ARE LOWER LEVELS OF ACETYLCHOLINE
*So we want to increase it!!!
Cholinesterase inhibitors may alleviate cognitive symptoms.
Symptoms of Alzheimer’s disease may be caused by…
CHRONIC ACTIVATION OF N-METHYL-D-ASPARTATE (NMDA) RECEPTORS BY GLUTAMATE which is an excitatory amino acid.
Excitatory glutamatergic neurotransmission via N-methyl-d-aspartate receptor (NMDAR) is critical for synaptic plasticity and survival of neurons.
- HOWEVER, excessive NMDAR activity causes EXCITOTOXICITY and promotes CELL DEATH, underlying a potential mechanism of neurodegeneration occurred in Alzheimer’s disease (AD).
Also a decreased level of catecholamines (Serotonin, Dopamine, norepinephrine) which may contribute to symptoms such as depression.
Medications for Alzheimer’s
DONEPEZIL and TACRINE are CENTRALLY ACTING ANTICHOLINESTERASE AND INDIRECT CHOLINERGIC AGONIST (parasympathomimetic)
- donepezil inhibits cholinesterase preventing the breakdown of acetylcholine
- donepezil enhances cholinergic function by increasing the concentration of acetylcholine
Adverse effects
- Diarrhea, nausea, vomiting, abdominal discomfort, dizziness, headache, anxiety, blurred vision, dry mouth and insomnia,
MEMANTINE is an NMDA RECEPTOR ANTAGONIST
- in alzheimer’s patient abnormal glutamatergic activities causes sustained activation of NMDA receptors which may lead to excessive calcium influx, neuronal dysfunction and cell death…
- memantine binds the NMDA receptor-operated cation channels inhibit the prolonged influx of Ca2+ ions
Medications for alzheimer’s disease TO KNOW
donepezil
tacrine
memantine
Parkinson’s Disease
Parkinson’s disease is the second most common NEURODEGENERATIVE disorder and the most common MOVEMENT disorder.
It is characterized by progressive LOSS of muscle control, which leads to TREMBLING of the limbs and head while at rest, stiffness, slowness, and impaired balance.
As symptoms worsen, it may become difficult to walk, talk, and complete simple tasks.
Affects 1 in 250 over the age of 40 and approximately 1% of those over age 65.
MEN are more commonly affected than women.
Parkinson’s Disease Symptoms
Symptoms may be mild at first but progress with time. For instance, you may have a mild tremor or a slight feeling that one leg or foot is stiff and dragging.
Symptoms may affect one or both sides of the body, and can include:
Slow blinking, Constipation, Difficulty swallowing, Drooling, Problems with balance and walking, No expression in the face (like you are wearing a mask), Muscle aches and pains
(SEE IMAGE)
The four primary symptoms of PD
- tremor, or trembling in hands, arms, legs, jaw, and face;
- rigidity, or stiffness of the limbs and trunk;
- bradykinesia, or slowness of movement; and
- postural instability, or impaired balance and coordination.
Cause of Parkinson’s Disease
Unknown (genes and environmental factors)
SUBSTANTIA NIGRA is important to initiation and control of muscular movement.
- healthy substantia makes enough dopamine, but when nerve cells in substantia die there is not enough dopamine made… causing movement disorders!!
LACK OF DOPAMINERGIC ACTIVITY in substantia nigra leads to imbalance between dopamine and acetylcholine.
Dopamine-producing cells in the brainstem are lost.
Dopamine plays important roles in EXECUTIVE FUNCTION, MOTOR CONTROL, MOTIVATION, AROUSAL, REINFORCEMENT, AND REWARD
(SEE IMAGE!!)
*(A) Normal and (B) abnormal balance between DOPAMINE and ACETYLCHOLINE.
Treatment of Parkinson’s Disease
No cure available
Drug therapy manages symptoms
PHARMACOTHERAPY ATTEMPTS TO REBALANCE DOPAMINE AND ACETYLCHOLINE BY:
- DECREASING MUSCARINIC ACTIVITY
- INCREASING DOPAMINERGIC ACTIVITY BY BLOCKING ITS BREAKDOWN OR MIMICKING ITS ACTION
Parkinson’s Disease Treatment
Carbidopa-levodopa.
- Levodopa, the most effective Parkinson’s disease medication, is a natural chemical that passes into your brain and is converted to dopamine.
Dopamine agonists.
- Unlike levodopa, dopamine agonists don’t change into dopamine.
- Instead, they mimic dopamine effects in your brain.
MAO-B inhibitors.
- They help prevent the breakdown of brain dopamine by inhibiting the brain enzyme monoamine oxidase B (MAO-B).
Anticholinergics may help control tremor and rigidity.
Catechol O-methyltransferase (COMT) inhibitors.
Deep brain stimulation.
Anticholinergic Drugs: Uses and adverse effects
Work by inhibiting muscarinic receptors and BLOCKING THE EFFECT OF ACETYLCHOLINE
Only centrally acting anticholinergics are used (benztropine (Cogentin), and trihexyphenidyl).
A number of anticholinergic drugs are available but side effects such as confusion and hallucinations occur, particularly in people over the age of 70.
Adverse effects
Common: anxiety, agitation, confusion, dry mouth, decreased sweating and heat release
Serious: urticaria, urine retention, paresthesias, sinus tachycardia
ANTICHOLINERGIC DRUG EXPOSURE AND RISK OF DEMENTIA
