Neuropharmacology Flashcards
Dementia
-Cognitive or behavioural symptoms that interfere with function
-patient suffer from decline in fuction
-not due to delirium or psychiatric illness
-associated with cognitive impairment in 2+ domains
• Umbrella term for a symptom of underlying disease; many underlying aetiologies
Epidemiology of demtia
- Typically a condition of older age (65+)
- Aging population means increasing prevalence
- Improved understanding, healthcare, education means decreasing incidence
- Currently about 500,000 Australians living with dementia
- Will be >1 million by 2028 without a medical breakthrough
- Second leading cause of death in Australia
- Cost $15 billion in 2018, will be $19 billion by 2025 and $37 billion by 2056
Alzheimer’s disease
- Most common cause of dementia
- Accounts for about 70% of cases of dementia
- About 30% of the population aged over 85 have AD pathology
Pathophysiology of AD
- Proteinopathy ( issue with protein) :Amyloid-mediated tauopathy
- Aetiology
- Sporadic, late onset (≥98%): failure of clearance of Aβ
- Carriage of APOE e4 only recognised genetic risk factor
- Likely other polygenic risk factors, under investigation
- Familial (extraordinarily rare): overproduction of Aβ
- Caused by a known mutation in APP, presenilin-1, or presenilin-2 genes
- Autosomal dominant, penetrance approaching 100%
- Environmental factors moderate symptom onset, progression
- 40% of cases of dementia potentially modifiable
amyloid Beta
- Chain of 40-42 amino acid peptides
- Cleaved from amyloid precurserprotein (APP) by β-and γ-secretase enzymes
- Aβ40-42 oligomers aggregate to form insoluble plaques on the surface of neurons
- Triggers a cascade of events that ultimately cause neurodegeneration
Aβ formation
- Two step process dependent on the action of two cleaving enzymes on APP (amyloid precusor protein)
- If APP is cleaved by β-secretase and then γ secretase, product is Aβ
- Oligomers are then released into the extracellular space
- Aβ oligomers are chemically “sticky”. They aggregate to form plaques on the cell surface
Aβ detection in vivo – amyloid detection test
- a PET scan with marker that bind to the Aβ
• CSF analysis
• Presumed inverse relationship between CSF Aβ and CNS Aβ
→ Reduced CSF Aβ a positive biomarker result for AD
• Blood test
• First published in 2018 (Nakamura, 2018)
• Preliminary results show the test can predict amyloid positivity as measured by PET with >80% specificity and sensitivity
• Replication and validation ongoing
• Cardiovascular and central nervous systems are functionally distinct
• Not as simple as measuring absolute levels of Aβ in the blood
• Protein expression affected by very many variables
Tau
- A protein involved in stablising microtubules of axons
- 6 different varieties (“isoforms”)
- Tau can be phosphorylated at a number of sites on the protein, which decreases its ability to bind microtubules
- Pathological tau becomes hyperphosphorylated, and aggregates into neurofibrillary tangles
- Implicated in many different neurodegenerative diseases (“tauopathies”)
Neurofibrillary tangles - formation
- normal Tau stabilizes microtubules
- Tau hyperphosphorylation causes microtuble depolymerisation
- Tau ologomers aggregation lead to formation of paired helical filament which lead to neural death and release of tau ologmer into extracellular environment
Neurofobrillary tangles – disease staging
- NFT Stages I-II (entorhinal stages) problem with memory fuction
- NFT stages III-IV ( Limbic stages) futher cognition impairment
- NFT Stages V-VI (Neocortical stage) demented
Tau detection in vivo
- Tau PET
- Tracer has to cross cell membrane, in addition to blood-brain barrier
- Tau tracer has to bind to the right conformation (isoform) of tau
- CSF analysis
- Quantification of levels of total and p-tau (specific to AD)
- Blood tests under development to measure tau in blood plasma
- Validation in real world clinical populations to commence in selected clinical settings in Australia and overseas this year
Neuronal loss in dementia
- Presence of Aβ and tau tangles causes activation of microglia (an immune response → inflammation) and, ultimately, apoptosis
- Precise interaction between Aβand tau unknown
- Cell death follows the pattern of tau deposition; begins in mesial temporal lobes
Pathological sequence of AD
• Aβ and tau → synaptic dysfunction → cell loss → cognitive and functional decline (dementia)
Temporal sequence of Aβ accumulation in AD
- It takes 12 years to go from no amyloid to “at risk” levels
- It takes 19 years to go from “at risk” to levels seen in AD
- It takes over 30 years to go from no amyloid to levels seen in AD
- …we have a 19 year window to intervene in the AD process in the hope of slowing, stopping, or reversing the pathology
Clinical syndrome of AD
- Exists on a spectrum
- Long preclinical phase
- Prodromal/mildly symptomatic (~3 years)
- Frankly demented (~5 years)
- Coincides with progression of pathology throughout the cortex
- Earlier stages: high level association cortex implicated, relative sparing of primary sensory and motor areas
- Later stages: disease impacts lower level sensory and motor cortex
- Leads to physical decline and frailty
- Terminal stages: patient bedridden, at risk of respiratory complications
Diagnostic criteria for probable
Alzheimer’s disease
- Person is demented
- Insidious symptom onset (over months to years)
- Clear history of cognitive decline (from informant or observation)
- Initial and predominant deficits in:
- Memory (amnestic presentation, typical onset)
- Language, visuospatial, or executive function (non-amnestic presentation, atypical onset)
- No other likely explanation (e.g. vascular disease, Lewy body disease, other neurological, psychiatric or systemic disease that might cause cognitive impairment)
AD-related cognitive changes
Memory impairment (typical onset)
• Insidious onset, recent memory difficulties
• A failure to learn and remember new information
• cf. errors of capture, or problems with retrieval
Patient’s subjective report of limited utility Navigation/orientation difficulties
• Getting lost
• Unable to keep track of time/place
Language decline
• Anomia (“without name”)
• Circumlocution
Clinical diagnosis of AD in practice
•decied base on Decline in cognition (usually) or behaviour causing functional impairment
• Estimate patient’s baseline
• Assess performance on multiple tests measuring all the key domains of cognition
• Compare performances to established normative data sets to determine impairment vs normal ageing
-if cognition has declined but the person is not demented it could be Mild Cognitive Impairment or Prodromal AD
Implications – why does timely clinical
diagnosis matter
- Dementia is progressive → permits future planning
- One day, that will include advanced decision making such as threshold for assisted suicide
- Considerations around fitness to drive, Mandatory reporting requirements to VicRoads
- Assessment of decision-making capacity Protection of the vulnerable/preservation of autonomy
- Access to possible treatments No point treating people after 20 years of damage has accumulated
- Relief of having a label/explanation
Prevention of AD
- Modifiable risk factors
- Probably modify rate of disease progression, symptom onset rather than the pathology per se
- Mechanisms sometimes unclear (e.g. deafness)
- The question of education and cognitive reserve
- What about brain training?
different method for Treatments for AD
Symptomatic relief
• Donepezil, rivastigmine, galantamine and memantine → not disease modifying
Anti-amyloid
• Antibodies (facilitate clearance) → promising; FDA approved Aducanumab in 2021
• BACE inhibitors/moderators (inhibit production) → liver toxicity
Anti-tau
• Antibodies → too early to tell
Downstream
• Promote BDNF/synaptic generation
• Remove iron, reduce oxidative stress
• Anti inflammatories, reduce immuno-mediated damage
Treatment for AD
The solution will be in rational combination therapy
-Early inhibition of production (avoids toxic overdosing) using β- and/or γ- secretase inhibitors/moderators
- Facilitation of clearance in those at risk :Genetic profiles, lifestyle factors
- Adjunct therapy to promote brain health
• Reduce inflammation
• Foster synaptic activity, neurogeneration, plasticity
• Waiting for symptoms is too late
• We will succeed
• In sporadic, late onset AD the clearance failure rate compared to non-AD is only 5%
• The discrete amount of Aβ in an AD brain is only 5mg
Signalling in the Brain: Neuron
-At rest the neuron has a negative charge, an action potential is triggered when the charge becomes sufficiently positive due to signal arriving at the dendrite (can be positive or negative)
-Signal received by dendrites & travels down the axon where the signal is sent to dendrites on the next neuron
Neuron fires (action potential) – All or none….
- single units of activity
Structure from brain to synapse
Brain & spinal cord have 100 billion neuron
-each nerone can fomr more than on synapse
~ 0.15 quadrillion synapses in the cortex
Cell membrane
- Neurons have a cell “membrane”that acts like a wall preventing things from entering or leaving the neuron.
- The cell wall as two layers with the fatty inside of each layer sticking together like a sandwich.
- Because of the fatty inside layer, fluids and other chemicals like neurotransmitters are not able to pass through.
Receptors
Receptors located on the outside of the cell membrane allow the released neurotransmitters to influence the post-synaptic neuron.
Two types of receptors:
- Ion Channels
- G-Protein coupled
Receptor specificity
Receptors are very selective (lock and key).
Each receptor can generally only be activated by one neurotransmitter (or a drug that is designed to mimic that neurotransmitter).
They also have a very specific function/action. When a neurotransmitter binds to the receptor this will trigger the same event every time (either opening a channel or triggering a second messenger event).
Ion Channels
Ion channels act like a “gate” for ions.
When a neurotransmitter binds to the receptor outside the neuron, this causes the gate to open and ions (positively and negatively charged molecules), can flow through.
Channels are normally “selective”and only allow one or a few types of ions to pass through when they are open (e.g. a calcium ion channel).
G protein-coupled receptor
G-Protein receptors work through second messengers.
When the neurotransmitter binds to the receptor it activates a “second messenger system”that can either open a channel or cause other things to change within the cell (e.g. DNA being transcribed and new proteins being made).
Neurotransmitter
A chemical substance released from a neuron at an anatomically specialised junction (synapse), which diffuses across a narrow cleft to affect one or sometimes two postsynaptic neurons, a muscle cell, or another effector cell.
Neuromodulation:
A chemical substance released from a neuron in the central nervous system, or in the periphery, that affects groups of neurons, or effector cells that have the appropriate receptors. It may not be released at synaptic sites, it often acts through second messengers and can produce long-lasting effects.
Neurotransmitter Vs Neuromodulators
§Neurotransmission: Either EXCITATORY or INHIBITORY and serves rapid (millisecond), precise, point to point communication.
§Neuromodulation: Describes slower (milliseconds to seconds) processes that alter the subsequent responsiveness of neurons.
Neuromodulation at presynaptic and post synaptic
§Presynaptic: Alters neurotransmitter release
§Postsynaptic: Alters neurotransmitter action (e.g., alters excitability/ firing pattern)
§Neuromodulation may cause changes in neural function or structure (i.e. sustained neuromodulator activity can drive changes in the brain related to synaptic plasticity).
Neurtransmitters/Neuromodulators (CNS)
Originate in small clusters of neurons (nuclei) deep within the brain stem. But are released throughout the CNS via long neuron
Neurotransmitters: Slow & Fast
§Synthesis and transport to the synapse is relatively slow.
BUT
§The neurotransmitter action is extremely fast because it sits ready for release.
Psychopharmacology
The study of drug induced changes in mood sensation, thinking & behavior.
Action of drug at the receptor
§Drugs act by “mimicking” natural neurotransmitters or
neuromodulators.
§Can act as AGONISTS activating the receptor like the
natural compound.
§Or can act as an ANTAGONIST blocking the receptor
and preventing the natural compound from activating it.
Cycle of Neurotransmitters
1 Synthesis 2 Release from synaptic vesicles 3 Binds to receptors 4 +/- influence on post synaptic neuron 5 Broken down by enzymes 6 reuptake of transmitter 7 formation & storage in synaptic vesicles
Drug Action on cycle of Neurotransmitters
Drugs can effect all stages
Synthesis interruption
-drug can affect different stage in the synthesis of neurotransmitter
Synthesis interruption
Neurotransmitter function can be altered by increasing or decreasing synthesis of the neurotransmitter
Non-traditional “neurotransmitters”`
DO NOT satisfy ALL criteria for a Neurotransmitter
§Present in presynaptic terminals
§Released from presynaptic terminals after neuron fires
§Existence of receptors on postsynaptic neurons
Hormones
§Signaling molecules produced by glands and
transported through the blood to regulate physiology
(muscles, neurons etc) and behaviour.
Psychology vs Pharmacology
§Pharmacology can effect psychology
Natural neurotransmitters and artificial drugs can clearly effect mood, cognition & behaviour
§Psychology can also effect pharmacology
Emotional or stressful events, thoughts and behaviour effect us BECAUSE they influence our neurotransmitters.
§Cognitive therapy and pharmacology acts on
the same brain!!
Glutamate & GABA
§Glutamate & GABA both believed to be the first to evolve and are found in very simple organisms
§Glutamate & GABA are the most common neurotransmitters in the CNS
§Glutamate & GABA both act as a “true” neurotransmitter – directly affecting the likelihood of the post-synaptic neuron firing
Glutamate
§Glutamate is the MAIN excitatory neurotransmitter in the brain (increasing likelihood of the post-synaptic neuron firing)
§The neurotransmitter released by ALL excitatory neurons.
§Estimated that over half of all brain synapses release Glutamate
Glutamate: Synthesis
§Glutamate = Glutamic Acid
§Glutamate is an amino acid that acts as a neurotransmitter in its “original” form but this amino acid does not pass the blood brain barrier so it still needs to be synthesized in the brain
§synthesized from glutamine which is released by cells neighboring the neurons
Neurotransmitters: Excitatory
§Found in most of the long projection neurons throughout the cortex.
§Excitatory connections are “point-to-point”.
§Many region-specific functions (e.g. connections along the visual pathways)
Glutamate: Receptors
§4 major types §3 are ion channels (ionotropic) - NMDA receptor - AMPA receptor - Kainate receptor §1 is G-Protein-coupled (metabotropic) - the metabotropic glutamate receptor
Glutamate: NMDA Receptors
It has at least 6 different binding sites so has lots of complex functions
§For example it only works if
1) there is also a glycine molecule (another amino acid) attached
2) if magnesium ion is NOT bound to inside
§The other binding cites modulate receptor function
NMDA Receptors: Alcohol
§Alcohol is an NMDA antagonist
§Reduction in glutamate is believed to contribute both to the general sedative effects & memory effects of alcohol
§Alcohol is also GABA agonist which further leads to brain inhibition.
