Neurophysiology Flashcards
What makes up the central nervous system?
Brain (cranium), brain stem and spinal cord (vertebral column)
Parts of the brain?
Groove (valleys): suclus (plural sucli)
Ridge (hills): Gyrus (plural gyri)
White matter in centre, grey matter around edges
Parts of the spinal cord?
White matter on outside, grey matter on the inside
What do sucli and gryri allow?
more cerebral cortex to be contained in a fixed volume
What makes up the grey matter?
cell bodies and dendrites (the cerebral cortex is grey matter)
What makes up the white matter?
axons (myelin that forms from the oligodendrocytes)
What are the protective layers that cover the brain and spinal cord meninges?
connective tissue
- dura mater (outer layer, tough)
- Arachnoid mater (web-like structure, middle layer)
- Pia mater (inner layer, soft)
What is meningitis?
Inflammation of the meninges (meningococcal bacteria if bacterial, can be viral)
What antibiotics are used for bacterial meningitis?
Benzylpenicillin (cefotaxime if allergic)
Where does CSF flow to protect the brain?
between arachnoid and pia maters (sub-arachnoid space)
no space between dura and arachnoid)
What is sub-arachnoid haemorrhage?
brain bleed (can be as result of injury)
How much of the spinal column does the spina cord cover?
2/3 (final 1/3 is individual neurons)
Which part of the spinal cord are epidurals and lumbar punctures carried out in?
lower third, higher up risk of damaging cord
Volume of CSF?
150mL - bathes CNS
Where is CSF produced?
choroid plexuses - capillary like structures in the ventricles
What is the structure/layout of ventricles in the brain?
Left and right lateral ventricles, that flow down to a third, then the fourth
How much CSF is produced per day?
400-500mL / day
Consequences of inadequate drainage for CSF?
hydrocephalus (fluid build up in the scalp)
Name a cause of inadequate drainage of CSF?
brain tumour - pushes on aquaduct and interferes with flow of fluid
What is the BCSFB?
Blood Cerebrospinal fluid barrier
What does the BCSFB consist of?
capillary endothelial cells (leaky) and ependymal epithelial cells (barrier)
What is the purpose of the endothelial cells in the BCSFB?
reglulate how much blood and ions can flow
Fucntion of the MRP?
multidrug resistance protein - pumps certain drugs back into blood (out of epithelial cell) to stop them penetrating the CNS
Function of the Pgp?
P-glycoprotein - pumps drugs into CSF
Composition of CSF?
Similar to plasma, with less protein
What are the ventricles?
Spaces in the brain that produce and circulate CSF
How are the four ventricles linked?
- Left and right ventricles sit in the respective hemispheres
- Connected to the third ventricle by the Foramen of Monro
- Third ventricle sits between the two hemispheres
- Third and fouth ventricles connected by the aqueduct of Sylvius (cerebral aqueduct)
- This then links down to the central canal via Foramen of Magendie (with expel to the subarachnoid space)
Structure of the BCSFB?
capillary endothelial cells surround the capillary so fluid can leak out
The ependymal cells then form the tight barrier
Function of the blood brain barrier?
Separate CNS from periphery
prevents hormones, metabolites, toxins etc from entering the CNS
secondary: CNS homeostasis
Which transporter transports L-DOPA in the BBB?
LAT1 - large neutral amino acid transporter
What happens to L-DOPA once it has been transported across the BBB?
converted to dopamine by decarboxylase
What other molecules are transported across the BBB by transporters?
Amino acids
Nucleosides
Glucose (via GLUT1)
Use of glucose inside the brain?
energy supply (for neurone function, amino acids etc)
How are large molecules transported in the brain, and examples?
Specialised transport systems
Insulin and transferrin (iron) are transported by receptor mediated transcytosis
What compounds does the BBB protect the brain from?
- circulating endogeneous compounds (neurotransmitters, hormones, metabolites)
- exogeneous toxins, pollutants
BBB impacts drug delivery to CNS
Structure of the BBB?
Primarily specialised endothelial cells that surround the capillary, tight junctions
These are then surrounded by pericytes and astrocytes
Which proteins are in the BBB that efflux drugs?
P-gp, BCRP, Multidrug resistance protein
What are occulin and claudin?
Act as a cement to tighten junctions, so only water soluble molecules and others that fit a certain criteria can penetrate
Why is the BBB a major obstacle for drug companies?
Body recognises drugs as toxins so efflux transporters prevent them from entering the CNS, so penetration is limited
Why isn’t Parkinson’s treated with dopamine directly?
Dopamine can’t cross the BBB
Why are brain tumours difficult to treat?
Any drugs administered orally or iv must cross the BBB, and many are substrates of the efflux transporters
For this reason, some drugs are administered intrathecally. Alternatively adminsitered into the tumour during surgery
Examples of drugs used to treat brain tumours?
Doxorubicin
Vinblastine
Vincristine
Methotrexate
All Pgp substrates
Difference between methotrexate and vincristine administration for treatment of cancers?
Methotrexate is IT - clear yellow
Vincristine is IV - clear colourless
What happens when Vincristine is administered IT (it happens)
it is a potent neurotoxin
Surgical emergency - aspirate CSF, irrigation, administer IT plasma
Why is IT plasma administered in Vincristine IT emergency?
Plasma is similar to CSF but contains more proteins which bind the vincristine
Examples of drugs that are not Pgp substrates?
Older drugs e.g. promethazine which enters the brain and causes sedation
How does a stroke cause brain damage?
Cell death releases IL-1B, which causes inflammation. leads to further brain damage
What effect does IL-1 have on cells?
Binds to IL receptor, cell signalling activates NFκb
What consequences does NFκb have on cells?
Release of IL-6 and TNF. both lead to inflammation and cell death
Which drug blocks IL-1B?
Anakinra - reduced signalling reduces damage
What is the pathology of Alzheimer’s disease?
Amyloid beta plaques found extracellularly in the brain
Also neurofibriliary tangles - tangled chains of proteins called Tau
Prevalence of Alzheimer’s disease?
Most common form of dementia, affects about 500,000 in the UK
1 in 50 65-70y
1 in 5 80y+
Higher incidence in females
What are the types of dementia?
Alzheimer's disease Vascular dementia Mixed dementia Lewy body dementia Fronto-temporal dementia Parkinson's disease dementia
Prevalence of early onset Alzheimer’s?
pre-65y
1-5% of cases
Which genes appear to have mutations in Early Onset Alzheimer’s?
Amyloid Precursor Protein Presenilin 1 (component of gamma secretase) Presenilin 2 (component of gamma secretase)
Which gene seems to have an involvement in late onset Alzheimer’s?
Apolipoprotein (ApoE)
What does ApoE do?
- transports cholesterol into neurones
- binds to amyloid beta, possibly regulates aggregation
- *4 form is a mutation and seems to produce a protein that is less effective at regulating the aggregation
Brief summary of the amyloid hypothesis?
APP is cut to produce amyloid beta, which then aggregates to form plaques
Evidence for the amyloid hypothesis?
APP gene is located on gene 21 Downs syndrome (trisomy 21) will invariably exhibit Alzheimer's by the age of 40
How is amyloid beta produced from APP?
- APP is embedded in the cell membrane
- usually cut by alpha and gamma secretase to release proteins that aid learning and memory
- when cut by beta and gamma secretase, produces amyloid beta
What happens to the amyloid beta monomer that causes damage?
- N-terminal peptide - causes neurone death
- Monomers form insoluble plaques, that lead to synapse disruption and cell death
- Amyloid beta ogliomers formed, which are toxic to neurones, disrupt function
Which part of the amyloid beta pathway is a therapeutic target being explored?
Aggregation of the monomers - if this can be prevented it halts the rest of the pathway
What is the Tau hypothesis?
- microtubules form a scaffolding and transport system for nutruents and molecules
- these microtubules are stabilised by Tau
- Hyperphosphorylated Tau stabilises causes neurofibriliary tangles (seen in Alzheimer’s) which destroys transport
Effect of Alzheimer’s on the hippocampus?
atrophy
- impairs new memory formation
Effect of Alzheimer’s on the amygdala?
atrophy
- impaired emotional recall
Effect of Alzheimer’s on the cortex?
thinning
- memories from longer ago lost
What is solanezumab?
MAb trialled for Alzheimer’s disease - neuroprotector
Failed clinical trials
