Dementia Flashcards

Question

What are the side effects of ChEIs?

Answer 1

Related to pharmacology Nausea, vomiting, diarrhoea Leg cramps, excess mucus production Bradycardia – monitor pulse (also increased risk of falls) Side effects with one does not mean with all

Answer 2

Licensed for mild to moderate dementia in Alzheimer’s disease. LogP 5 (low water-solubility) Greater selectivity acetylcholinesterase Once daily dosing Low side effect profile Peak concentration 3 to 4 hours T1/2 = 70 hours Linear pharmacokinetics Food does not affect absorption 93 to 96% protein bound Metabolised in liver CYP450 Renal excretion Few clinically significant interactions, consider bradycardia and CYP inhibitors/inducers

Answer 3

Licensed for AD and mild to moderate dementia in Parkinson’s disease LogP – ca. 2 Inhibits both acetylcholinesterase and butylcholinesterase Twice daily dosing, also available as daily patch Low side effect profile, especially with patch Monitoring – patient’s body weight should be monitored whilst being treated with rivastigmine T1/2 approximately 2 hours Inhibition lasts 10 hours Renal excretion No hepatic metabolism Little protein binding

Answer 4

Licensed for mild to moderately severe dementia in Alzheimer’s disease Enhances response of nicotinic receptors to Ach T1/2 approximately 7-8h Starting dose is 8mg/day, titrating to max of 24mg/day Twice daily dosing liquid or once daily modified release capsules Low side effect profile Avoid if eGFR is less than 9mL/minute/1.73 m2

Answer 5

As the disease progresses the amount of Ach produced will be less than at pre-treatment and individual patient performance will decline, eventually to a stage where the agent will seem to have little clinical effect.

Answer 6

NMDA-receptor antagonist Protects the neurone from excessive calcium ion influx Significant improvement in cognition, function and global outcome Useful in behavioural problems Licensed for moderate to severe AD Dose 5mg day increased by 5mg per week until 20mg dose Half life is 80 hours Reduce dose in moderate renal impairment (40-60ml/min/1.73m2) Avoid if eGFR less than 5ml/min/1.73m2 Renal excretion probably relies on cation-transport proteins. Increasing the urinary pH can dramatically affect the elimination of the drug (by a factor of 7-9) Monitor if changes in diet

Answer 7

Establish links with Alzheimer’s Soc and any local charities Make it clear that pharmacies are dementia friendly. Posters, DF badges etc. Recognition of possible symptoms of dementia (e.g. poor short term memory; forgetfulness etc) especially when responding to symptoms and refer as appropriate Awareness of medicines that can exacerbate or cause confusion – mainly anticholinergic agents. Early access to – information, treatment, care and support networks Reversible causes can be eliminated or treated Make the most of remaining abilities Explain to family and friends – plan for the future Easier to determine subtype at early stages and treat accordingly Show empathy, offer privacy, signpost to support Advice around behaviour changes and aggravating factors eg. Constipation, pain, infection, physical/psychosocial factors

Answer 8

Declarative - daily episodes, words and meanings, history Emotional - preferences and aversions Procedural - motor skills, associations, priming clues, puzzle solving

Answer 9

Donald Hebb (1949) - when two neurones are active, so that one repeatedly releases neurotransmitter at the same time as its postsynaptic partner is firing action potentials, then that synapse will become stronger. “cells that fire together, wire together” Synapses strengthened by intense activity memory depends on populations of interacting neurones pattern of strengthened synapses defines memory

Answer 10

Increase in the strength after repeated stimulation is called Long Term Potentiation (LTP)

Answer 11

Postsynaptic - More AMPAr - More sensitive AMPAr - More synapses Presynaptic - Increased release - More release sites - More vesicles

Answer 12

Phosphorylation of AMPAr by PKC Insertion of new receptors by CaMKII. Also synthesis of new receptors Retrograde messenger - nitric oxide - presynaptic changes

Answer 13

The NMDAr is a glutamate receptor that plays a role in synaptic plasticity, learning, and memory. It is an ion channel that allows calcium, sodium, and potassium to flow into or out of neurons upon activation by glutamate, but excessive activation can lead to cell damage and neurodegenerative diseases. One form of memory depends on NMDAr - induced by NMDAr activation - expressed by AMPA receptors - maintained by changes in number/sensitivity of postsynaptic AMPAr and structural changes - also maintained by presynaptic alterations of glutamate release

Answer 14

anticholinesterases - donepezil (Aricept), galantamine agonists - nicotine, arecoline Stimulants - amphetamine, methylphenidate, modafanil, caffeine 5HT drugs – particularly 5HT6 antagonists GABAA receptor blockers - inverse agonists – suritozole AMPAkines - positive AMPAr modulators - piracetam, IDRA-21 mGluR drugs – particularly mGluR5 positive allosteric modulators

Answer 15

Amnesia drug induced head trauma - temporary or permanent Retrograde or anterograde Dementias Loss of multiple memory categories Inability to form new memories Associated with general cognitive decline Memory impairment first presenting symptom

Answer 16

Neuritic plaques (NP) - extracellular - amyloid--protein Neurofribrillary tangles (NFT) - intracellular - abnormal cytoskeletal protein Tau Primarily affect glutamate and acetylcholine neurones and terminals Aberrant function - synapse loss - neuronal death - brain shrinkage

Answer 17

90 % of AD cases are sporadic -secretase may be enhanced - environmental, disease, inflammation Genetic mutations identified in early onset AD (< 65 years) In presenilin genes - excess -secretase activity – make more A42 which is MOST likely to form plaques Genetic risk factor in late onset ApoE4 mutations - increased aggregation

Answer 18

Cholinesterase inhibitors - cholinergic neurones damaged early donepezil, rivastigmine, galantamine Enhance ACh at nicotinic and muscarinic receptors Small improvements in cognition Memantine Non-competitive NMDA receptor blocker slight improvements in cognition

Answer 19

Secretase inhibitors - in trials Anti-amyloid-beta vaccine / monoclonal antibodies – in trials Anti-tau vaccine / monoclonal antibodies – in trials Copper and zinc chelators - metal ions promote plaque formation – toxic Growth factors - not feasible for routine therapy Antioxidants – limited evidence – eg. Vitamin C, flavinoids Statins – some epidemiological evidence - cholesterol promotes amyloid deposition

Answer 20

High - sensory and association neocortex, basal ganglia - for planning strategy Medium - motor cortex, cerebellum - for tactics, prep and direction Low - brain stem, spinal cord - execution

Answer 21

The motor cortex is located in the frontal lobe of your brain. It generates electrical signals that control movement. Primary Motor Cortex: Directly controls specific muscles for voluntary movements. Premotor Cortex: Plans movements and coordinates muscle groups.

Answer 22

This is the major pathway for voluntary movement of the limbs. Upper motor neurons originate in the motor cortex, and most of them cross over at the level of the medulla in the brainstem. This means that the left motor cortex controls muscles on the right side of the body and vice versa. These neurons descend through the lateral column of the spinal cord and synapse with lower motor neurons in the spinal cord, which then send signals to the muscles. Fine motor control

Answer 23

Controls movements of the face, head, and neck. These neurons end in the brainstem rather than the spinal cord.

Answer 24

The signals from the motor cortex travel down the spinal cord and exit through nerves that connect to muscles. Sometimes, spinal reflexes occur before the signal even reaches the brain, like if you touch something hot and pull away quickly.

Answer 25

The basal ganglia are a group of structures deep within the brain that play a crucial role in the regulation and coordination of movement. They help initiate, modulate, and fine-tune voluntary movements, ensuring they are smooth, purposeful, and properly executed. The basal ganglia are involved in various functions, including motor control, habit formation, learning, and even emotions. Helps initiate and regulate movements (think of it as the "brake" and "gas" for movement control

Answer 26

Helps with balance and coordination, ensuring the movement is smooth.

Answer 27

This is another smaller pathway that also helps control limb movements, particularly in the upper limbs. It starts in the red nucleus (a structure in the midbrain) and crosses over to the opposite side of the body in the brainstem. It plays a role in coordination of motor actions, often complementing the corticospinal tract.

Answer 28

Vestibulospinal Tract Reticulospinal Tract Tectospinal Tract The ventromedial pathways control more gross movements and movements involving posture, balance, and coordination. These pathways mainly influence the muscles of the trunk and proximal (closer to the body) muscles of the limbs, helping with activities like walking, standing, or maintaining balance.

Answer 29

This pathway originates in the vestibular nuclei in the brainstem, which receive information from the inner ear (about balance and head position). It helps control muscles that keep you upright and maintain balance, especially in response to changes in body position or movement. It does not decussate and influences both sides of the body equally.

Answer 30

The reticulospinal tract originates in the reticular formation, a network of neurons in the brainstem that is involved in arousal, attention, and motor control. It helps regulate posture, muscle tone, and automatic movements, such as those required for walking. The reticulospinal pathway also plays a role in anticipatory adjustments to posture in response to changes in the environment.

Answer 31

This tract originates in the superior colliculus of the midbrain, which is involved in visual processing and coordinating head and eye movements. It is particularly important for orienting the body toward visual or auditory stimuli. Like the vestibulospinal tract, it helps with coordinating movements of the head and neck in response to sensory stimuli.

Answer 32

Striatum Globus Pallidus Substantia Nigra Subthalamic Nucleus

Answer 33

Caudate nucleus: Involved in cognitive functions, learning, and memory. Putamen: Primarily involved in motor control and movement coordination.

Answer 34

External segment (GPe): Involved in modulating signals between the basal ganglia and other brain regions. Internal segment (GPi): Plays a more direct role in motor control, sending inhibitory signals to the thalamus, which then influences movement.

Answer 35

This is a small structure in the midbrain that is critical for movement control. The pars compacta of the substantia nigra produces dopamine, which is crucial for facilitating movement by promoting activity in the striatum. The pars reticulata of the substantia nigra also sends inhibitory signals to the thalamus, helping regulate movement.

Answer 36

Located beneath the thalamus, the subthalamic nucleus plays an important role in modulating the output of the basal ganglia, particularly through its connections with the globus pallidus. It is involved in generating and controlling movement, particularly in the initiation of voluntary actions.

Answer 37

The direct pathway promotes movement by disinhibiting the thalamus. When the striatum receives input from the cortex, it sends inhibitory signals to the internal segment of the globus pallidus (GPi). This inhibits the GPi’s usual inhibitory signals to the thalamus. The thalamus becomes more active, which then sends excitatory signals to the motor cortex, leading to movement initiation.

Answer 38

The indirect pathway works to suppress unwanted movements or inhibit excessive movement. The striatum, upon receiving input from the cortex, inhibits the external segment of the globus pallidus (GPe). This leads to disinhibition of the subthalamic nucleus, which sends excitatory signals to the GPi. The GPi, in turn, increases inhibition to the thalamus, reducing the thalamic signals to the motor cortex and preventing unwanted movements.

Answer 39

Parkinson’s Disease: Degeneration of dopamine-producing neurons in the substantia nigra leads to difficulty initiating movement (akinesia), tremors, and rigidity. Hypokinetic. Huntington’s Disease: A genetic disorder that causes damage to the striatum, leading to involuntary movements (chorea), impaired coordination, and cognitive decline. Hyperkinetic. Tourette Syndrome: Characterized by repetitive, involuntary movements and vocalizations (tics), Increased activity in nigro-striatal pathway Treated with dopamine D2 receptor-antagonists Dystonia: A movement disorder caused by abnormal activity in the basal ganglia, resulting in muscle spasms and abnormal postures. Obsessive-compulsive disorder: Lesions in caudate/putamen - repetitive motor responses, Treated with SSRIs

Answer 40

1817 - James Parkinson – shaking palsy Progressive - dementia - cognitive decline 0.1% of population, disease of the elderly Rare at < 40 yrs > 50 yrs - 1% Increased risk with head trauma Genetic susceptibility? Environmental and drug induced Survival time ~10yrs Drugs do not alter progression

Answer 41

akinesia - the absence or reduction of movement bradykinesia - slowness of movement rigidity - resistance to passive movement tremor - pill rolling poor balance speech problems progressively depression, anxiety, sleep disturbance, cognitive dysfunction

Answer 42

Primary - loss of DA cells from SNc Degeneration of nigro-striatal pathway Genetic mutations Mutant synaptic proteins (-synuclein) - aggregation Mutant Parkin (ligase) - prevents proteolysis Protein aggregation - inclusion (Lewy) bodies Oxidative stress - mitochondrial dysfunction Cell death Parkinsonism - drug induced Neuroleptics MPTP

Answer 43

Loss of DA neurones - imbalance in direct and indirect pathways increases activation of Gpi via indirect Decreases inhibition via direct Increases inhibition of thalamus Switches off thalamo-cortical pathways Loss of cortico-spinal output Decreased movement, rigidity etc

Answer 44

Increase DA synthesis Oral L-DOPA - first line Converted to DA by DOPA-decarboxylase Combined with peripheral decarboxylase inhibitors (carbidopa, benserazide). DA receptor agonists bromocriptine, pramipexole, apomorphine COMT inhibitors - entacapone MAO inhibitors - selegiline DA release Combination therapy with L-DOPA Deep brain stimulation STN Disruption of GPi

Answer 45

1872 - George Huntington - “On Chorea” Progressive degenerative Cognitive decline before motor Low incidence 0.01% Appears between 30 and 50yrs Inherited disorder - 50% chance of defective gene

Answer 46

Chorea - involuntary jerking Grimacing Balance and gait problems Cognitive decline, memory loss, depression Swallowing and speech Death 10-20 years following diagnosis

Answer 47

Primary - cell death in caudate/putamen Impaired striatal-nigral and striato-pallidal transmission Nigro-striatal preserved progressive - degeneration of GP Huntingtin protein - normal function unclear Mutant huntingtin - genetic defect Expanded repeats of codon for glutamine Dense protein aggregates migrate to nucleus Apoptosis - cell death

Answer 48

Loss of caudate neurones decreased inhibition of GPe increased inhibition of STN Decreased excitation of GPi/SNc Decreased inhibition of thalamus Increased thalamo-cortical activity Increase in cortico-spinal output Hyperkinesia, facial tics etc

Answer 49

No cure Baclofen (antispasticity) D2 antagonists (e.g. chlorpromazine) Treat symptoms e.g. depression

Answer 50

Ataxia Fine motor control, gait and co-ordination Multiple types and causes - genetic, trauma, stroke, alcohol and drugs Degeneration of cerebellar cortex, spino-cerebellar pathways, ponto-cerebellar pathways, deep cerebellar nuclei, cerebellar-cortico pathways No cure - treat the symptoms