Case 6 Flashcards
What are the two types of astrocytes?
Fibrous astrocytes - round in white matter
Protoplasmic astrocytes - round in grey matter
What is the precursor of astrocytes called?
Radial glial
What does the cytoskeleton consist of?
Microtubules, microfilaments and neurofilaments
What are the different types of neurones?
Unipolar - sensory
Pseudounipolar - sensory
Bipolar - interneuron
Multipolar - motor/interneuron/pyramidal cell
Which neurones are myelinated?
Some in PNS and those in the Sympathetic nervous system
Where is neurotransmitters produced?
In the neurones cell body and then actively transported to axonal end
What is an electrotonic potential?
Non-propagated local potential caused by a local change in ionic conductance - it reduces as it spreads across the membrane
Used to trigger AP
What is an Action Potential?
Propagated impulse
How is a resting potential set?
Set through Na/K pump and also the open potassium ion channels which increases the membrane permeability of potassium.
The is more potassium inside the cell than outside (opposite for sodium)
RP = -70mV
What happens during depolarisation?
Depolarising stimulus causes the activation of voltage-gated sodium ions, if threshold is met, influx of sodium causes an AP
At +30mV the sodium channels become inactive before returning to resting state
What happens during repolarisation?
Voltage-gated potassium channels open slowly and causes efflux of potassium reducing the membrane potential
What is hyperpolarisation?
This is a process where a high stimulus is required to cause AP because of slow return of potassium channels to close state
What are the two gates of the sodium voltage-gated sodium channels?
M-gate - activation gate outside the cell
H-gate - inactivation gate inside the cell
RP = m-gate closed and h-gate open Depolarisation = m-gate open and h-gate open Repolarisation = m-gate open and h-gate closed
(Potassium only has h-gate)
What is the all-or-none law?
Once threshold is met an AP is produced and further increase in intensity of a stimulus won’t produce changes in AP
What are the two refractory periods?
Absolute - no stimulus will excite the nerve (due to inactivation of Na channel)
Relative - stronger than normal stimuli can cause excitation (due to K channel)
What are the two types of receptors?
Ionotropic - ion channels
Metatropic - g-protein coupled
In metatropic, the g-protein will activate ion channels or enzymes that generate 2nd messengers - there are then slower and longer lasting than ionotropic
What are the two types of demyelinating disease?
Primary demyelination - myelin sheath damage without axonal damage
Secondary demyelination - myelin sheath damage resulting from axonal damage
What are the CNS and PNS demyelinating disease to know?
CNS: MS and Vitamin B12 deficiency
PNS: Gullain-Barre Syndrome
What is MS?
Disease characterised by inflammation, demyelination and gliosis with lesions seen in CNS white matter
It may be relapsing (85%) or progressive (10-15%)
What are the symptoms of MS?
Loss of or changes in sensitivity (tingling, pins and needles, numbness)
Muscle weakness, pronounced reflexes, spasms, difficulty moving
Incoordination: ataxia, speech and swallowing problems (dysarthria and dysphargia) and visual problems (nystagmus, optic neuritis or dyplopia)
Depression and unstable mood
What is the epidemiology of MS?
1/800 in UK
Onset 20-40yo
Risk = low levels of vitamin D, exposure to human herpes virus and Epstein-Barr virus , smoking and stress
What are the types of MS?
- Relapsing and remitting (85-90%) - relapses (symptoms worsen) then complete or partial recovery and then remission (symptoms don’t worsen)
- secondary progressive - progression of disease following RRMS
- Primary Progressive (10-15%) - gradual progression from onset with no remissions or relapses
- progression relapsing (<5%) - progresses gradually but interrupted with sudden relapses
What are the three characteristics of MS
Inflammation, demyelination and
Lesions (plaques)
What happens during inflammation?
An infection causes damage to BBB which allows T-cells into CNS - there is recruitment of lymphocytes and monocytes > the chemokines released cause adhesion molecules on lymphocytes and monocytes which interact with Endothelial cells on BBB activating expression of MMP to degrade barrier leading to swelling and activation and infiltration of macrophages and lymphocytes that directly attack myelin sheath within CNS
Cytokines and antibodies are also recruited
What is the demyelination process?
Relapse:
Th-1 and Th-17 activated by IL-12 (over production of IL-12 =inflammation) which then attack myelin sheath (oligodendrocytes)
Remission:
Oligodendrocytes cells can’t fully repair so CNS gets stem cells but the new formed myelin is thin and not as effective so remission causes worsening until scar-like plaques (sclerosis) builds around damage axons
What do Th1 and Th17 cells do?
Th 1 secrete IFN-gamma for macrophages
Th-17 promoter leukocyte recruitment
Where do lesions tend to form?
White matter in:
Optic nerve, corpus callosum, cerebellum, brainstem, basal ganglia and spinal cord
What is Optic Neuritis?
Diminished visual acuity, dimness, or colour desaturation in centre of vision
Afferent pupillary defect
Pallor of optic disc (optic atrophy)
How is MS diagnosed?
Requires documentation of two or more episodes of symptoms and two or more signs that reflect pathology in anatomically noncontiguous white matter tracts of the CNS
What are diagnostic tests for MS?
MRI - shows increased vascular permeability due to breakdown of BBB, and lesions
Evokes Potentials Test - shows electrical activity of brain
CSF - elevated levels of IgG antibodies, oligoclonal bands via electrophoresis, and proteins that are breakdown products of myelin
How do Glucocorticoids (Methylprednisolone/Prednisone) work?
They inhibit the generation of vasodilators and function of APC; they reduce prostaglandin, leukotriene and platelet-activating factor synthesis that result from activation of phospholipase A2; reduce expression of COX-2
reducing inflammation
Side effects: hyperglycaemia, decreased resistance to infection, swelling of face, weight gain, fluid retention, oedema, hypertension
How do Beta-Interferon work?
Inhibit T cells activation, prevent T cells proliferation and block T cells migration across BBB
Treat relapsing and remitting disease via subcutaneous injection (alternating days) preventing relapse rates and increased lesions
What do Immune-modulators do?
Glatiramer Acetate/Copaxane
bind to MHC class 2 preventing binding of other antigen
Compete with myelin basic protein (MBP) for T cell receptor
Inhibiting activation of MBP-reactive T cells suppressing inflammatory response
What does Fingolimod/Gilenya do?
For relapsing-remitting MS
Bind to sphingosine 1-phosphate receptor 1 blocking capacity of autoreactive lymphocytes to egress from lymph nodes - reducing migration to CNS
What does Natalizumab/Tysabri do?
Monoclonal antibody that inhibits migration of leukocytes into CNS by preventing binding to VCAM-1
Used in severe relapsing remitting MS
Associated with progressive multi focal leukoencephalopathy (PML) due to reactivation of John-Cunningham Virus (JVC)
What are the two immunosuppressants?
Teriflunomide and Dimethyl Fumarate
What is depression?
A state of low mood and aversion to activity that can have a negative effect on a person’s thoughts, behaviour, feelings, world view and physical well-being
It is a symptom not a psychiatric disorder lasting 4-12months
How is Major Depression Diagnosed?
PHQ-9
Questionnaire of symptoms and freq. Over 2weeks
What are symptoms of MDD?
Negative cognition (feeling worthless, hopeless) Psychosis (psychotic guilt and catatonic retardation)
What are risks of MDD?
Life stress, family history, earlier age of onset
What are the two groups of monoamines?
Catecholamines - dopamine, noradrenaline, adrenaline
Indoleamines - serotonin
What are the precursors of monoamines?
Dopamine - Tyrosine to L DOPA
Noradrenaline - hydrolysis of dopamine
Adrenaline - conversion from noradrenaline
Serotonin - tryptophan
How do we intake the monoamines precursors?
Tyrosine and Tryptophan is taken from diet
What are the enzymes for serotonin and noradrenaline breakdown?
MAO-A
MAO-A and COMT
There are two types of MAO:
• MAO-A: deaminate noradrenaline, adrenaline, serotonin, melatonin and dopamine
• MAO-B: deaminate phenylethylamine and dopamine
What are the reuptake transporters for serotonin and noradrenaline?
5-HTT,SERT
NET, NAT
What are the receptors of noradrenaline and serotonin?
Alpha receptors - a1 (stimulators) a2 (inhibitory)
Beta receptor - b1,2,3 (stimulators)
5-HT family
What is the interaction between serotonin and noradrenaline?
Noradrenaline acts on noradrenergic receptors on serotonin systems stimulating or inhibiting the release of serotonin
(The two systems act individually)
What is the MOA of Resperine?
Used to control Blood Pressure
Irreversible VMAT blocker so prevents transport of serotonin and catecholamines through vesicles from cytoplasm
Causes depression
What is the MOA of Imipramine?
SNRI antidepressant that inhibits reuptake of serotonin and noradrenaline
What is the MOA of Iproniazid?
Antidepressant that irreversibly inhibits MAO so increase levels of monoamines (especially serotonin)
Moclobomide reversibly inhibits MAOs
A tyramine diet is required while on MAOI to prevent increase in blood pressure
Side effects:
Dry mouth, nausea, headache, drowsiness, high BP, weight gain
What are the three type of antidepressants?
Tricyclics Antidepressants (TCAs):
• block reuptake of noradrenaline, serotonin and Dopamine
• amitriptyline and clomipramine
Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs):
• reversibly block SERT and NET
• imipramine and venlafaxine
Selective-Serotonin Reuptake Inhibitors (SSRIs):
• reversibly block SERT
•fluoxetine, sertraline, paroxetine, fluvoxamine, escitalopram, citalopram
What is Mirtazapine?
Alpha-2 adrenergic receptor antagonist
Blocks the negative feedback loop to inhibit the release of noradrenaline and serotonin therefore there is an increase of both
What does the amygdala do?
Part of the Ventral Neural System
Modulates visual and attentional processing, particularly of facial expression
In MDD it is overly activated when shown sad stimuli but under-activated when shown positive stimuli
What is the function of the hippocampus?
Part of the Dorsal Neural system
Deals with memory consolidation
In MDD there is a reduction in the hippocampal volume leading to a decrease in memory consolidation
What does diasthesis mean?
Prédisposition to illness
What is the diasthesis-stress hypothesis of mood disorder?
Hyperactivity in HPA system
Hypothalamus releases increase of CRH > stimulates increased ACTH release from anterior Pituitary gland > stimulates increased cortisol release from adrenal cortex
Cortisol dysregulates amygdala function and increases activity of MAO decreasing levels of serotonin, noradrenaline and dopamine
It also causes reduction in BDNF resulting in reduction in neurogenesis and decreased hippocampal volume
Which genes are linked with depression?
5HTT genes
Short/short = greater risk of developing depression
Short/long = most common in population
Long/long = lesser risk of developing depression
How is depression treated?
- Mild - low intensity psychosocial intervention
- moderate - ADs + high-intensity psychological intervention such as CBT
- ECT - most effective for depression and involves inducing seizures activity in the temporal lobes
- psychotherapy - CBT, IPT, PST
What is coping?
Process of managing stressors that have been appraised as taxing or exceeding a person’s resources
What are types of coping?
Approach
Avoidance
Problem focused
Emotion focused
