Week 12 Neuro
What is the amyloid cascade hypothesis relating to Alzheimer's disease?
*Amyloid Cascade Hypothesis ¥ Most accepted theory ¥ Initiated by overproduction and extracellular deposition of Aβ and the intracellular deposition of NFT o Debate continues about role of Aβ vs. tau proteins vs. NFT - Inflammation is an important part of this process also
What are the 3 types of neuronal repair, what do they involve and where do they occur?
3 Types of Neuronal Repair Neurons in PNS and CNS 1. Peripheral nerve regeneration - Mature neurons are amitotic, but if soma intact, peripheral axon of CNS or PNS neuron may regenerate - Requires axon growth, guidance (to regenerate appropriately) and synapse formation - Easier to achieve, most clinically successful 2. Restoration of damaged CNS neurons - Requires ability to regrow dendrites axons and synapses - More complex and requires more help from other neurons and glia, growth factors etc. - Usually fails in the CNS because glial cells produce mediators which inhibit cell growth - A small lesion can cause damage to thousands of neurons in the same area (harder than repairing those that are along a single axis) 3. Complete genesis of new neurons (neurogenesis) - Occurs rarely, mechanisms not understood - Requires presence of pluripotent stem cells, appropriate environmental factors (e.g. chemicals, growth factors) etc. • Injury of an axon is pretty easy to fix • If whole neuron is injured, they may be eliminated as they are not able to recover, but the new diagram shows that the existing neurons have created new connections to compensate (post-recovery) • C - there are some stem cells and they can develop into new neurons (as seen in the post-recovery diagram) - this doesn't' happen much as there are processes that work against this
Where are the ACh CNS pathways located and what are their functional roles?
ACh CNS Pathways • Widely distributed • All parts of forebrain and cortex, midbrain, brainstem • Major nuclei in nucleus basalis (basal forebrain) • Striatum (basal ganglia) • Septohippocampal nucleus (hippocampus) • Functional roles include memory, arousal, motor control
How does Alzheimer's disease progress and what are some of its symptoms?
Alzheimer's disease progression ¥ Neuronal damage spreads over years (5-10 years) ¥ Memory loss is usually first sign - executive and cognitive function ¥ Increasing trouble with planning or organizing ¥ Confusion, poor judgement, language and thought deficits, restlessness, agitation, depression, behavioural changes ¥ Inability to self-care (e.g. toileting, brushing their teeth, etc.), full dependence on others ¥ Loss of awareness of environment ¥ Weight loss, seizures, loss of bladder & bowel control ¥ Increased infections ¥ Death usually occurs from aspiration pneumonia, respiratory failure
What is Autonomic dysreflexia, when does it occur and why does it occur?
Autonomic Dysreflexia • occurs in SCI patients, due to neuroplastic changes in spinal circuits • noxious afferent stimulus activates massive SNS response - only below lesion - typically vasoconstriction • increased BP triggers baroreceptor reflex from brainstem - activates parasymp above lesion - unable to inhibit symp below lesion • overall result is increased parasymp above, increased symp below • some responses not well understood, eg characteristic sweating of face • hypertension is main issue requiring treatment • even tyring to defacate can cause this response in some patients • overstimulated SNS response - it is exaggerated - get vasoconstriction, etc.
How can calcium influx cause cell injury?
Calcium influx • cellular Ca++ normally tightly regulated • increased Ca++ alters mito membranes • activation of enzymes (phospholipases, endonucleases, proteases etc) that damage cellular components including membranes and cytoskeleton • mitochondrial dysfunction • oxidative damage • triggers apoptosis • too much calcium is deadly - activates enzymes that will breakdown ATP, membranes, etc.
What is Juvenile myoclonic epilepsy, when is it usually diagnosed and what are its causes?
Clinical Syndrome - Juvenile myoclonic epilepsy • common form of idiopathic generalised epilepsy • usually diagnosed between ages 12 - 18 • brief episodes of involuntary muscle twitching usually in early morning (may be due to hormonal levels or different activity in the brain) • most patients also have generalized seizures and some have absence seizures - can have multiple different types of seizures • genetic cause • alteration in genes which code for ion channels
What is dementia and what is its prevalence? What is its projected incidence in 2050? What is it characterised by and what is its most common type?
Dementia Alzheimer's disease is the most common cause of dementia Dementia: range of diseases characterized by impairment of brain functions, including language, memory, perception, personality and cognitive skills. - Umbrella term of a set of symptoms including impaired thinking and memory - issues other than AD can cause dementia • Epidemiology - Projected incidence 950,000 in Aust in 2050 - Alzheimer's disease is the most common (70%) - Second most common cause is stroke/vascular disease - Prevalence increases with age - up to 20% >85 - very important - Seen mostly in Western developed countries - lots of money goes into research because of this - Neurodegenerative disease • Characterized by progressive impairment of memory and cognitive function - May lead to vegetative state and early death (loss of body function, pneumonia, aspiration of contents, etc.) • Alzheimer's disease - the most common type of dementia - This isn't reversible (is degenerative) whereas some forms of dementia ae reversible or temporary
What are the definitions of seizure and epilepsy and what are the 2 main classes of epilepsy and their subclasses? How do they differ?
Epilepsy ¥ Seizure: episodes of high frequency cortical discharge ¥ Epilepsy: condition where there is repetitive seizure activity (1% of population) - single event = one seizure (some people without epilepsy may have one seizure in their lifetime) - epilepsy are when seizures occur repeatedly - about altered electrical signals in the brain Epilepsy Classification: (based on characteristics of seizure) - uses more focused descriptive terms ¥ Partial seizures (focal): o Localised discharge (focal) of electrical activity o Simple - no loss of consciousness ♣ Symptoms depend on region affected, e.g. aura (could be a visual sensation or some other sensory sensation), muscle spasms, numbness o Complex - transient aberrant behaviour ♣ Impaired consciousness - where the patients might appear to be drunk (patients may not be treated properly because of this) o Partial seizures secondarily generalized - starts of as a partial seizure and then becomes a generalised seizure o Only affect 1 hemisphere of the brain, but quickly involve other areas of the brain ¥ Generalized seizures o Involve whole brain (both hemishperes) o Generalized tonic-clonic - 'grand mal' seizures - where patient has repetitive chronic contractions ϖ Tonic comes first - all muscles stiffen ϖ Clonic - arms and usually legs begin to jerk rapidly and rhythmically ϖ Consciousness returns slowly - There are 2 phases - a tonic then a clonic phase (where there is lots of jerking) o Absence seizures - 'petit mal' seizures - can be as simples as a patient having a staring fit - there is a loss of consciousness, but there are no muscle movements and they don't fall to the floor o Tonic seizures ϖ Body, arms or legs stiffen while consciousness is usually preserved ϖ Most often occur during sleep, usually affect most or all of brain; affecting both sides of the body o Atonic seizures ϖ Muscles suddenly lose strength - eyelids may droop and head may nod - person may drop things to fall to ground ϖ Person usually remains conscious ϖ Start in childhood and last into adulthood ϖ Usually <15 seconds o Clonic and myoclonic seizures - common (myoclonic cause sudden muscle jerks) ϖ Myoclonic seizures - brief shock-like jerks of a muscle or group of muscles ϖ Rapidly alternating contraction and relaxation ϖ Usually don't last more than a second or two ϖ Usually cause abnormal movements on both sides of body at same time o Status epilepticus - several epileptic fits that can be life threatening ¥ These last 4 can depend on the types of muscle movements experienced ¥ Can have patients that have many different types of seizures ¥ Medications are targeted at a specific type of seizure as there are potentially different causes
What are some of the causes of epilepsy?
Epilepsy Causes: - Development alterations in neuron populations - Lesions, injury - Alterations in ion channels (channelopathies) ϖ Channelopathies are generally genetic disorders that affect the function of ion channels - Large genetic basis - Altered electrolytes - (especially those affecting membrane potential) - pH changes (some drugs which cause pH changes can affect the ways neurons function) - Glucose (ketogenic diet is a popular type of therapy in children with epilepsy) ϖ Special high-fat, low carbohydrate diet that helps to control seizures ϖ Long-chain triglyceride diet = common form of this diet - provides 3-4g of fat for every 1g of carbohydrates and proteins ϖ Produces ketones in body (when body uses fat as its source of energy) ϖ Higher ketones often lead to improved seizure control - Enhanced excitatory neurotransmission - Reduced inhibitory neurotransmission Many drugs increase seizure risk Anything that is involved in AP transduction is potentially involved in epilepsy (e.g. sodium, potassium channels and important NT's in the CNS being glutamate and GABA) - These are targeted by antiepileptic drugs
Generally, how is generalised epilepsy initially managed?
Initial Management of Generalised Epilepsy • If the patient has one seizure, that is not necessarily epilepsy - you do tests to see whether there is epilepsy • Try to avoid things that may trigger seizures • Management is complex
What is the ketogenic diet and what are the proposed mechanisms of helping with epilepsy?
Ketogenic Diet • high fat, low carbohydrate and moderate protein • leads to production of ketone bodies from the oxidation of fat as primary source of metabolic energy • proposed mechanisms include: - changes in the levels of glutamate and GABA - KBs inhibit glutamate decarboxylase and stimulate the synthesis of GABA - KBs activate ATP-sensitive K+ channels - diet enhances overall cellular bioenergetics and reduces oxidative stress. - Ketone bodies potentially alter some of the enzymes involved with GABA and glutamate - has an inhibitory effect
What do most injuries to the CNS and PNS involve? What is the difference between repair in the CNS and PNS? What is recovery after brain injury caused by?
Nerve injury and repair ¥ Most injuries to the CNS/PNS involve damage to axons (because axons take up most of the space outside of the brain) ¥ If neurons die - generally not replaced - There are some stem cells in the brain and nervous system, but it doesn't generate new axons a lot ¥ Limited ability of brain to alter and repair ¥ Brain does not produce large numbers of new neurons postdevelopment ¥ Some repair does occur after injury ¥ In PNS, axon show robust regrowth and re-innervation of sensory or motor targets ¥ In CNS few neurons can regrow damaged axons / dendrites ¥ Recovery after brain injury usually due to reorganisation of existing intact circuits (functional reorganisation): - 'Use-dependent plasticity' - Undamaged neurons can develop other connections when needed after injury and lead to functional recovery e.g. following a stroke - over a number of years, the patient is able to regain some function - good at making new connections, but not generating new neurons
What are some of the pathological mechanisms in epilepsy? What endogenous factors may have a role?
Pathological mechanisms in epilepsy: ¥ Result of a shift in the normal balance of excitation and inhibition within the CNS - During a seizure, have overwhelming excitation that can spread to other areas of the brain ¥ Focal seizures usually associated with structural abnormalities of the brain - Local activity - Could be in response to injury, stroke or channelopathy (genetic change which leads to a functional change in an ion channel) ¥ Generalized seizures usually result from cellular, biochemical or structural abnormalities - Due to s change that is more widespread - Could for example be a congenital abnormality ¥ Many causes of seizures and epilepsy - May be able to identify triggers, but not a cause - can determine what is physically responsible for it ¥ Complex interplay between endogenous factors (e.g. genetics), epileptogenic (something known to cause epilepsy) factors (e.g. injury), and precipitating factors (things bringing on seizures e.g. stress, sleep deprivation (e.g. in myoclonic seizures), hormonal changes, toxins, drugs, diet etc.) - Hormonal changes - in women, seizure may be associated with a particular stage of the menstrual cycle - Drugs can alter the seizure threshold for those with a predisposition for epilepsy
What are the characteristic pathologic changes involved in the pathophysiology of AD? What are they caused by? What can neuronal cell death be caused by?
Pathophysiology of AD: * Characteristic pathologic changes include increased deposits of: o Beta-amyloid protein Aβ (amyloid plaques)* ♣ Due to impaired processing of amyloid precursor protein by sercretases ♣ Plaques build up around neurons, leading to neuronal degeneration ♣ The larger proteins that are usually snipped into smaller parts are snipped incorrectly - produce aggregates - Tau protein (neurofibrillary tangles)** - This happens inside cells - Both are seen post-mortem in patients with AD - Progressive loss of neurons, especially cholinergic neurons in the hippocampus, frontal cortex Cholinergic neurons are usually first affected, but other neurons are killed off also (e.g. dopamine, 5-HT and glutamate neurons) - A number of drugs for AD work on the cholinergic neurons o Neuronal cell death can may be due to: ♣ Glutamate excitotoxicity (may be due to viruses or infections) ♣ Abnormalities of mitochondrial function
What happens as a result of peripheral nerve regeneration when a peripheral axon is crushed or severed?
Peripheral nerve regeneration • When a peripheral axon is crushed - Recovery rapid as damaged distal segment provides path for axon regrowth - Good recovery because the neuron is still connected to the target - the cell body can send appropriate proteins along the axon to help with recovery • When a peripheral axon is severed (axotomy) - Distal segment degenerates (Wallerian degeneration) - Macrophages phagocytose axon fragments - If you sever cell body from axon - the bit of axon distal to the sever will degenerate as it doesn't have any information from the cell body - lose guidance process from cell body ϖ Macrophages come along and eat the old axon and glial cells form a scaffold to form the axon along - clear a new pathway for the axons to grow • Schwann cells proliferate, secrete growth factors, adhesion molecules and provide a growth conduit to guide axons • Neuron soma switches to growth mode • Axon filaments grow through regeneration tube • Greater distance between severed ends-less chance of regeneration - it is harder to connect • If degenerated, axons must also replace synaptic connections at targets • Schwann cells are producing myelin for the new axon to grow
How are damaged CNS neurons restored and what are the 3 main stimuli responsible for cell death in the CNS? - IMPORTANT What is excitotoxicity and what other abnormal processes can occur? Why is their prolonged clearing?
Restoration of damaged CNS neurons • Little regrowth of CNS axons, other than those that project into the periphery • Most CNS injury involves neuronal cell death: - Trauma - Hypoxia (due to ischemia) - e.g. during stroke - Neurodegenerative diseases The 3 main stimuli responsible for cell death in the CNS • Excitotoxicity - Damage leads to overactivity of Glutamate systems - Increased calcium in the cell - leads to excitotoxicity - Leads to cell death - Overactivation of glutamate receptors allows high levels of calcium ions to enter the cell which activates a number of cell structure destruction routes - IMAGE - shows one of the proposed mechanisms by which both excitotoxicity and inflammation can lead to apoptosis ϖ Yellow balls - they are not glutamate going into the neuron, but calcium going into the neuron ϖ Inflammation - cytokines are rleased ϖ The 2 mechanisms combine on Bcl-2 • Central glial cells less sensitive to injury and proliferate - Glial scarring - Blocks axon regrowth • Have lots more glial cells in the brain than neurons (10:1) • Some processes of apoptosis are responsible for neuronal cell death • Cytokines released during cell damage process converge on molecular pathway at Bcl-2 - have caspases which then trigger the process of apoptosis • Apoptosis more like suicide, necrosis more like homocide • Prolonged clearing - don't have the macrophages coming along and clearing the path for regrowth
What are the roles of Tau and NFTs in the pathophysiology of Alzheimer's disease?
Role of Tau and NFTs ¥ Normally tau binds to and stabilizes microtubules o Supporting axonal transport of organelles, neurotransmitters etc throughout neuron - the things it synthesises may not be able to make it to the synapse from the cell body ¥ Hyperphosphorylation of tau decreases affinity for Microtubules - they dissociate as they don't want to stick on the microtubules - Don't know how this happens ¥ MTs disassemble and neurons lose support and die ¥ Directly induces formation of aggregates (which lead to NFTs) ¥ NFTS remain after cell dies KNOW THE BASICS OF HOW THE PLAQUES AND TANGLES FORM AND BE ABLE TO CONNECT IT WITH PHARMACOLOGY - most drugs are not actually addressing the cause of AD
What are the 3 main barriers to CNS near-generation?
Three Main Barriers to CNS Neuro-regeneration 1. CNS injury usually causes neuronal cell death (if the cell body itself is damaged) 2. Glial cells actively inhibit axon growth and cell repair a. Oligodendrocytes have growth-inhibiting proteins that prevent CNS axon regeneration b. Astrocytes at injury site form scar tissue containing chondroitin sulfate that blocks axonal regrowth (physically blocks the reconnection of axons following injury) 3. Stem cells are present in adult brain, but with limited ability to divide, migrate and differentiate
How is Autonomic Dysreflexia treated immediately and in the long-term?
Treatment Immediate management • non-pharmacological measures • remove the cause • nitrates (sublingual) • capropril (sublingual) • nifedipine discouraged due to adverse effects long-term prophylactic management • selective alpha-1 adrenoceptor antagonists • botulinum toxin, capsaicin, anticholinergics, surgery, anaesthesia
What are the 3 different types of Alzheimer's Disease and what can the last one be associated with?
Types: • Familial form • Sporadic forms • Early onset - Associated with several gene defects: Trisomy 21 (Down Syndrome), genes for presenilin-1, ApoE (alteration in this - has something to do with transporting cholesterol and facilitating neurodegeneration)
Where does excitotoxicity fit in to AD? What drugs can be used to inhibit this?
¥ It is belived to contribute to neuronal cell death in AD ¥ Downstream of beta amyloid and NFTs but also considered to be a potential separate mechanism in response to other factors ¥ Drugs such as NMDAr antagonist memantine work via inhibiting excitotoxicity ¥ Preferentially blocks excessive NMDA receptor activity without disrupting normal activity ¥ Uncompetitive, low-affinity, open-channel blocker ¥ Enters and blocks the receptor-associated ion channel preferentially when it is excessively open ¥ important mechanism in neuronal cell death ¥ occurs in response to trauma, hypoxia, and in neurodegenerative diseases eg SCI (spinal cord injury), stroke, TBI (traumatic brain injury), hearing loss, AD, PD, MS, amyotrophic lateral sclerosis (ALS) ¥ caused by processes which lead to increased glutamate (eg metabolic, neuron damage, glial dysfunction) or alter response of glutamate receptors - could be due to a genetic change - could be metabolic ¥ many factors (hypoxia, mitochondrial damage, disordered glucose metabolism etc) can increase RMP → removal of voltage-dependent Mg2+ block of NMDA receptors ¥ excess stimulation of NMDA (most associated with this) / AMPA → massive Ca++ influx - these receptors need to be activated and the cell be depolarized - damage to the neuron can lead to this
What activates the abnormal beta-amyloid pathway in Alzheimer's disease?
¥ β secretase is also known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) ¥ Mechanisms responsible for activation of amyloidogenic pathway are unknown ¥ Mutation in gene for apolipoprotein is best established genetic risk factor for late-onset AD ¥ Role of ApOE in brain not known, may help breakdown beta amyloid ¥ Isoform ApoE-4 not effective - formed as a result of genetic mutation ¥ Also Down Syndrome
What are some potential markers of AD?
• Some of the changes have been there 20-30 years before the symptoms have appeared - may be able to predict the formation of AD earlier on in life due to these potential markers of AD
What is necrosis and what is it caused by?
• pathological process of cell death - homicide • important in how neurons die in neurological diseases • main pathway of cell death from common insults eg. ischemia, toxins, infectious agents, trauma • involves unregulated enzymatic digestion of cell components • occurs when damage to membranes is severe • enzymes leak out of lysosomes into cytoplasm and digest the cell • membrane falls apart • cell contents also leak out through damaged plasma membranes and initiate inflammation
Outline the pathophysiology of AD...
• something going on where the normal processed to get rid of abnormal proteins is not functional proteins proteins is not functional • Oligmers clump to produce a plaque
What is apoptosis and what is it caused by? What are its characteristics?
• tightly regulated type of cell death - the cell realizing it has to kill itself - does this in a controlled manner to avoid collateral damage • active, energy dependent process • occurs in specific situations • serves many normal functions and is not necessarily associated with pathological injury • serves to eliminate cells that are no longer needed, and to maintain a steady number of various cell populations in tissues • occurs when a cell is deprived of growth factors or DNA or proteins are damaged beyond repair • cell kills itself • mediated by the activation of caspases • characterized by enzymatic degradation of proteins and DNA
