Lecture 67 Alzheimer’s Disease Klassen ALZHEIMER’S DISEASE: • Most common cause of dementia; 3 rd most common neurological disorder • Irreversible, progressive and degenerative brain disease that slowly destroys memory & thinking skills • NOT part of normal aging o Majority have first symptoms after age 60 o Risk of developing AD increases with age • AD has high morbidity and mortality rate STANDARD DISEASE PROGRESSION: Mild Stage Description • As AD progresses, memory loss continues & changes in other cognitive abilities appear Symptoms • Getting lost • Trouble handling money and paying bills • Repeating questions • Taking longer than before to complete normal daily tasks • Poor judgment • Losing things or misplacing them in odd places • Mood and personality changes Other • In most people with AD, symptoms first appear after age 60 o AD is diagnosed at this stage Moderate stage Description • In moderate AD, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought Symptoms • Increased memory loss and confusion • Problems recognizing family and friends • Inability to learn new things • Difficulty carrying out tasks that involve multiple steps (such as getting dressed) • Problems coping with new situations • Delusions and paranoia • Impulsive behaviour Advanced stage Description • People with severe AD cannot communicate and are completely dependent on others for their care Symptoms • Inability to recognize oneself or family • Inability to communicate • Weight loss • Seizures • Skin infections • Difficulty swallowing • Groaning, moaning, or grunting • Increased sleeping • Lack of control of bowel and bladder Other • The most frequent cause of death for people with AD is aspiration pneumonia GENETICS AND AD: Familial Sporadic • < 5% early-onset, single gene inheritance • 15-25% late-onset, complex inheritance • 75% • Majority late onset • Same sx as familial • Risk factors for sporadic AD: o Aging, hormonal changes o Head injuries o Vascular diseases, inflammation o Genetic predisposition o Exposure to metals, like Cu++ and Zn++ • 1 st degree relative risk = 3-4x general population MAJOR STRUCTURAL CHANGES IN AD: NEUROFIBRILLARY TANGLES: • Bundles of twisted threads that are the product of collapsed neural structures • Contain abnormal forms of tau protein o Heavily hyper-phosphorylated proteins o Cause aggregation and precipitation of the cytoskeleton AMYLOID PLAQUES: • Dense deposits of deteriorated amyloid protein, surrounded by clumps of dead nerve & glial cells o Plaques accumulate in vulnerable brain regions (neocortex, hippocampus, amygdala basal, forebrain) • B-amyloid is the initial cause of the pathophys that leads to dementia o Amyloid plaques “likely” contribute to the later stages of pathology NEURONAL DEATH: reduced brain volume, especially in cortex and hippocampus PATHOGENIC HYPOTHESIS IN AD: these mechanisms are NOT mutually exclusive
Transcript
Lecture 67 Alzheimer’s Disease Klassen
ALZHEIMER’S DISEASE:
• Most common cause of dementia; 3rd most common neurological disorder
• Irreversible, progressive and degenerative brain disease that slowly destroys memory & thinking skills
• NOT part of normal aging o Majority have first symptoms after age 60
o Risk of developing AD increases with age
• AD has high morbidity and mortality rate
STANDARD DISEASE PROGRESSION:
Mild Stage
Description • As AD progresses, memory loss continues & changes in other cognitive abilities appear
Symptoms • Getting lost
• Trouble handling money and paying bills
• Repeating questions
• Taking longer than before to complete normal daily tasks
• Poor judgment
• Losing things or misplacing them in odd places
• Mood and personality changes
Other • In most people with AD, symptoms first appear after age 60 o AD is diagnosed at this stage
Moderate stage
Description • In moderate AD, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought
Symptoms • Increased memory loss and confusion
• Problems recognizing family and friends
• Inability to learn new things
• Difficulty carrying out tasks that involve multiple steps (such as getting dressed)
• Problems coping with new situations
• Delusions and paranoia
• Impulsive behaviour
Advanced stage
Description • People with severe AD cannot communicate and are completely dependent on others for their care
Symptoms • Inability to recognize oneself or family
• Inability to communicate
• Weight loss
• Seizures
• Skin infections
• Difficulty swallowing
• Groaning, moaning, or grunting
• Increased sleeping
• Lack of control of bowel and bladder
Other • The most frequent cause of death for people with AD is aspiration pneumonia
GENETICS AND AD:
Familial Sporadic
• < 5% early-onset, single gene inheritance
• 15-25% late-onset, complex inheritance
• 75%
• Majority late onset
• Same sx as familial
• Risk factors for sporadic AD:
o Aging, hormonal changes
o Head injuries
o Vascular diseases, inflammation
o Genetic predisposition
o Exposure to metals, like Cu++ and Zn++
• 1st degree relative risk = 3-4x general population
MAJOR STRUCTURAL CHANGES IN AD:
NEUROFIBRILLARY TANGLES:
• Bundles of twisted threads that are the product
of collapsed neural structures
• Contain abnormal forms of tau protein
o Heavily hyper-phosphorylated proteins
o Cause aggregation and precipitation of
the cytoskeleton
AMYLOID PLAQUES:
• Dense deposits of deteriorated amyloid protein,
surrounded by clumps of dead nerve & glial cells
o Plaques accumulate in vulnerable brain
regions (neocortex, hippocampus, amygdala basal, forebrain)
• B-amyloid is the initial cause of the pathophys
that leads to dementia
o Amyloid plaques “likely” contribute to the
later stages of pathology
NEURONAL DEATH: reduced brain volume, especially
in cortex and hippocampus
PATHOGENIC HYPOTHESIS IN AD: these mechanisms are NOT mutually exclusive
Lecture 67 Alzheimer’s Disease Klassen
PRINCIPLE PATHOPHYSIOLOGICAL HYPOTHESES
Cholinergic hypothesis
• Acetylcholine (ACh) is an important neurotransmitter in brain regions involved in memory
• Alzheimer’s patients have decrease in nicotinic and muscarinic ACh receptors in CNS o Cortical neurons receive less innervation less likely to be depolarized by synaptic signals
• Cholinergic defects correlate with cognitive decline and disease severity o Anticholinergics known to impair memory with increased effect with age
• LIMITATIONS o Decreased acetylcholine may be non-specific o Abnormalities in other chemical systems (GABA, glutamine, serotonin)
Amyloid hypothesis
1. Amyloid precursor protein (APP) is cleaved by a series of secretases a. Presenlin (PSEN1 & PSEN2 genes) are subunits of γ secretase which aberrantly cleaves APP
2. Aβ-42 (nonsoluble fragment of the APP protein) accumulates and is deposited outside the cell 3. The nonsoluble or “sticky” nature of Aβ-42 facilitates aggregation of protein fragments (including apoE) into plaques 4. Plaques accumulate outside the cell neuronal death
Tau hypothesis
• τ (tau) protein = microtubule-associated protein that acts as a 3D “railroad tie” for the microtubule (which is responsible for axonal transport) o cytoskeleton is stabilized by Tau proteins
• Accumulation of phosphate on the tau proteins cause “paired helical filaments” (PHFs) that accumulate and lead to neurofibrillary tangles (NFT) o Hyperphosphorylated Tau cannot stabilize microtubule cells lose stability & Tau form tangles o Impaired axonal transport is the probable cause of cell death
• Focus on MAPT gene (microtubule-associated protein tau)
• Not in favour anymore
Presenilin hypothesis
1. Elevated levels of Aβ-42 inhibit PS function, mimicking effect of PS mutations 2. Resulting production of Aβ-42 is enhanced by partial loss of PS and γ-secretase activity 3. Aβ-42 mediated inhibition leads to greater impairment of PS function 4. Loss of PS activity results in:
a. Synaptic dysfunction (deficits in synaptic plasticity) b. Alterations in molecular signalling events (impairment of NMDA receptor-mediated functions) c. Ultimately age-related, progressive neurodegeneration characterized by loss of synapses, dendrites, and neurons; astrogliosis; and tau
hyperphosphorylation
Memantine hypothesis
1. Aβ oligomers interfere with NMDA signalling increase in internalization of postsynaptic NMDAR subunits 2. Aβ interferes with EAAT (glutamine transporter) increasing glutamate in the synaptic cleft 3. Abeta oligomers complex with presynaptic nicotinic receptors 4. Glutamate spillover activates extrasynaptic NMDAR 5. Increases calcium influx activates metabolic pathways responsible for neuronal shrinkage and synaptic loss 6. Activation enhances hyperphosphorylation of tau leading to neuronal degeneration and cell death
TREATMENT OF ALZHEIMER’S DISEASE STUDY SLIDE 40 !!! (starred)
THERAPEUTIC GOALS FOR ALZHEIMERS:
• Therapy aimed at prolonging the pt’s cognitive function
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