lecture 67 alzheimer’s disease klassen - rxnotes...2. resulting production of aβ-42 is enhanced...
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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
(improve memory, functional status, slow progression,
delay or prevent onset)
o Secondary goals include symptomatically treating
psychiatric & behavioral abnormalities
• Therapy has not shown to prolong life, cure AD, halt or
reverse the pathophysiological degradation of disease
PRINCIPLE STRATEGIES: normalize NT systems in AD (cholinergic & glutamatergic systems are
involved in learning/memory)
MILD TO MODERATE AD MODERATE TO SEVERE AD
Cholinesterase inhibitor (galantamine, rivastigmine, donepezil)
Memantine (an NMDA antagonist), donepezil
• May delay or limit short term symptomatic progression
• May help control some behavioral sx
• Delay progression of some of the sx of moderate to severe AD
• Can enable pts to perform ADLs longer
CHOLINESTERASE (AchE) INHIBITOR THERAPY IN AD:
MCI • Benefits cognition?
Early-stage dementia • Benefits cognition
Moderate-severe dementia
• Benefits cognition
• Preserves global status
• Preserves Activities of Daily Living (ADL)
• Benefits behavior?
All approved for mild-moderate AD; donepezil also approved for severe AD
Galantamine • Competitively & reversibly inhibits AchE
• Absorption is rapid & complete (F = 80-100%)
• Linear PK; t1/2 = 7 hours
• Not shown to alter the underlying dementia process
Rivastigmine • Pseudo-inhibitor of both butyl- & acetyl- cholinesterase
• F = 40% (oral 3 mg dose)
• Can cross the BBB
Donepezil • Selective reversibly non-competitive inhibitor of AChE
• Most widely used drug for AD; only treatment approved by the FDA for all stages of AD
• F = 100%
• Can cross the BBB
SEs • NVD; weight loss; loss of appetite; muscle weakness
MEMANTINE THERAPY FOR AD:
• Excitotoxic neuronal cell NMDA glutamate receptors causes
excessive Ca2+ influx
• Memantine (NMDA antagonist) reduces excitatory glutamate NT in
brain reduced exposure to excitotoxic levels of glutamate
o Preferentially blocks excessive NMDA receptor activity
without disrupting normal activity
o Uncompetitive, low-affinity, open-channel blocker; enters
ionotropic pore when prolonged opening
o Fast off-rate so will dissociate and permit normal synaptic
transmission just not prolonged activation
• SEs: constipation, confusion, dizziness, headache, hallucinations,
coughing, HTN
MCI • Role unknown
Mild-moderate dementia • Inconsistent effects
Moderate-severe dementia
• Benefits cognition
• Preserves global status
• Preserves Activities of Daily Living (ADL)
• Benefits behavior
Used in moderate to severe diseases; not recommended in early stages
Lecture 67 Alzheimer’s Disease Klassen
THERAPEUTICS IN THE PIPELINE:
INTERVENTIONS THAT “MIGHT” IMPACT AD:
• Antihypertensive therapy
• Hormonal agents (estrogen)
• NSAIDs (naproxen and celecoxib)
• High-dose vitamin B,
• Folic acid supplementation
• Statins
• PPAR-gamma agonists
• Fish oil, omega-3 fatty acids
• Weight control, healthy diet
VITAMIN E:
• Antioxidant – may be useful because
of the accumulation of free radicals
associated with AD
• Favorable side effect profile; low cost
• Impaired hemostasis, fatigue,
nausea, diarrhea, abdominal pain,
and thinning of the blood
• Increased mortality in older patients
GINKGO BILOBA:
• Increased blood flow, decreased viscosity of blood, antagonizing platelet activating factor receptors, increased tolerance to anoxia, inhibiting MOA, anti-infective properties, preventing damage of membranes caused by free radicals
• If used for dementia should be used as soon as
deterioration of cognitive functioning occurs
• Side effects are typically mild & rare
• Herbal products are typically poorly standardized
HUPERZINE A:
• An alkyloid isolated from the Chinese club moss, Huperzia serrata
• Reversibly inhibits AChE
• Administered 50-200 mcg po bid-qid
• May be more promising for symptomatic treatment of AD
• Promising product from clinical studies, but lack of product purity
• Concurrent use with other available AChE inhibitors should be avoided
METHYLTHIONINIUM CHLORIDE:
• Inhibits Tau aggregation via:
1. Blocking formation of Tau oligomers and their conversion to PHFs
(paired helical filaments) tangles
2. Solvating/dissolving Tau oligomers and paired helical filaments into
the short truncated monomers
a. Truncated Tau monomers become susceptible to proteases and
are of a size that can be cleared efficiently through the
proteasomal clearance pathway
AD AND IMMUNOTHERAPY: amyloid “vaccine” reduces plaque burden and memory loss in transgenic mouse model of AD
ACTIVE IMMUNIZATION:
• 1st generation vaccine: Elan Phase II clinical trial of active immunization with an aggregated
Aβ in adjuvant (AN1792)
o Study terminated prematurely: 18/300 developed a sterile meningoencephalitis
related to cerebral T lymphocyte
o 59 (20%) developed adequate Aβ response
▪ 1 year follow-up of those who at least 1 dose of AN17912 showed that
patients with an anti- Aβ antibody response exhibited slower rates of
cognitive & functional decline and reduced CSF concentrations of Tau protein
compared with non-responders
• 2nd generation vaccines and antibodies both target linear AA sequences found in APP and
in amyloid deposits
o Avoid T-cells (T-helper 1) activation causing meningoencephalitis
▪ N-terminal short Aβ peptides with Th2 adjuvant or Th2-stimulating molecules
o Antibodies against normal human proteins can cause autoimmune SEs
• 3rd generation vaccines use antibodies that target structures specific to amyloid aggregates
and that do not react with normal human proteins
Active immunization activates body’s immune system to produce antigen-specific antibodies. Aβ
conjugated to foreign T-cell delivered alongside an immune system booster (adjuvant). Humoral
immune response is generated.
PASSIVE IMMUNIZATION:
• Monoclonal antibodies in development are designed to
target 1 of 3 domains of the Aβ protein: the n-
terminus, the middle portion, or the c-terminus
o Efficacy and/or safety may differ by domain
• Elan/Wyeth, bapineuzumab (AAB-001) is a humanized
monoclonal antibody to N-terminus of Aβ
o In 2012 it failed to produce significant cognitive
improvements in patients with 2 major trials
o Did have significant lowering of key biomarkers
of AD, amyloid brain plaque and phosphorylated
Tau protein in CSF
Passive immunization bypasses the need for the body to
mount an immune response to produce antigen-specific
antibodies.
In both active and passive Aβ immunization, anti-Aβ
antibodies bind Aβ, targeting the peptide for clearance.