S3C7 (2.0) Flashcards
What is SPECT scanning?
Three-dimensional (tomographic) images of the distribution of radioactive tracer molecules Gamma emitting radioisotope Cheap Convenient Poor spatial resolution
What is PET scanning?
Positron emitting radioisotopes
Expensive
More effort
Good spatial resolution
What is CT scanning?
X-rays round body Quick Cheap Convenient Involves radiation Poor quality
What is MRI scanning?
Magnetic donut Slow Expensive More effort No radiation High quality
What is the epidemiology of parkinsons?
Male predominance
Prevalence increases with age
Onset ~60 yo
What is parkinsonism?
A syndrome featuring bradykinesia and either resting tremor or rigidity (or both)
What are the risk factors for Parkinson’s?
Familial history - 10-15% cases Environmental factors - e.g. Exposure to manganese Diet/ metabolism Low levels Vit D High iron intake Obesity Structural damage History of traumatic brain damage
What medication can cause secondary parkinsonism?
Familial history - 10-15% cases Environmental factors E.g. Exposure to manganese Diet/ metabolism Low levels Vit D High iron intake Obesity Structural damage History of traumatic brain damage
What metabolic disorders can cause parkinsonism?
Wilson disease - an autosomal recessive metabolic disorder of copper (due to ATP7B gene mutation) in which both impaired binding to its transporter protein (ceruloplasmin) and biliary excretion increase free serum copper, leading to accumulation in the body
What is the pathophysiology of parkinsons?
Progressive dopaminergic neuron degeneration in the substantia nigra and the locus coeruleus
Dopamine deficiency at the respective receptors of the striatum with interrupted transmission to the thalamus and motor cortex
What causes the depressive symptoms of parkinsons?
Serotonin and noradrenaline depletion (in the Raphe nuclei)
What causes the dyskinesia in parkinsons?
Acetylcholine surplus in nucleus basalis of Meynert
What causes lewy bodies ?
Aggregates of misfolded α-synuclein and hyaline eosinophilic globules
What is the pathogenesis of cell death?
Oxidative stress Intracellular calcium accumulation with excitotoxicity Inflammation Mitochondrial dysfunction (apoptosis) Proteolytic stress
What are the clinical features of parkinson’s?
Unilateral onset with persistently asymmetrical course but may progress on the contralateral side
Bradykinesia/ akinesia
Resting tremor (4-6Hz)
Rigidity
What frequency is the resting tremor?
4-6Hz
What is the tremor like in parkinsons?
Pill rolling tremor that subsides with voluntary movements but increases with stress Typical in hands May involve Legs Jaw Lips Tongue
What is bradydiadochokinesia?
Alternating antagonistic movements are conducted unusually slowly
What is rigidity?
Increased and persistent resistance to passive joint movement that is independent of speed of movement
What is the froment maneuver?
Facilitates the evaluation of rigidity, especially in early stages
What is cogwheel rigidity?
Most likely caused by the overlay of increased muscle tonus and tremor in PD patients
Muscles in an extremity give way in successive jerks when passively move
What is the parkinsonian gait?
Shuffling gait with quickened and shortened steps
5-8 extra steps to turn around
What is the glabellar reflex?
Primitive reflex elicited by tapping of the glabella, the area between the eyebrows, causing the subject to close his or her eyes
positive in PD patients and babies
What causes bradykinesia?
Increased inhibitory output to central pattern generators in brainstem
Increased inhibitory output to thalamus and motor cortex
Abnormal 20 Hz (β band) oscillations in basal ganglia circuit
What causes peripheral rigidity?
Reduced inhibition from type Ib fibres
Overactive type II fibres
Increased activity due to peripheral stimulation
What causes central rigidity?
Altered activity in GABA and Ach interneurones
Altered inhibition in indirect pathway
Increased responsiveness of STN/GPi firing to peripheral stimulation
What % of PD patients do not have a tremor?
30%
What drugs can be used to treat PD?
Levodopa
Dopamine Agonists
MAO-B Inhibitors
What surgery can be used for PD?
Bilateral subthalamic nucleus (STN) or globus pallidus interna (GPi) stimulation may be used.
What is co-beneldopa made of?
Levodopa
Benserazide
What is benserazide?
a peripherally-acting DOPA decarboxylase inhibitor.
This is combined with levodopa to reduce peripheral side effects.
Benserazide cannot cross the BBB and so doesn’t prevent the effects of levodopa in the brain.
What is Levodopa?
A precursor of dopamine
Crosses BBB and is decarboxylated into dopamine
What are the two main side effects of L-dopa?
Involuntary writhing movements (dyskinesia)
Rapid fluctuations in clinical state
What is selegiline?
MAO-B inhibitor
Inhibition of MAO-B protects dopamine from extraneuronal degradation.
Combination of selegiline and levodopa is more effective than levodopa alone in relieving symptoms and prolonging life.
What is the striatum comprised of?
Caudate and putamen in primates Medium spiny neurones 96% striatal neurones GABAergic +/- neuropeptides Interneurons GABAergic Cholinergic (large aspiny neurones)
What neurotransmitter is used in the corticostriatal pathway?
Glutamate
What is the role of the
direct dopamine pathway?
D1 receptor
Dynorphin precursor (PPE-B)
Facilitation of desired movements
What is the role of the indirect dopamine pathway?
D2 receptors
Enkephalin precursor (PPE-A)
Inhibition of unwanted movements
Which dopamine pathway prefers tonic dopamine release?
D2R
Which dopamine pathway prefers phasic dopamine release?
D1R
Where is ACh found?
NMJ Preganglionic autonomic synapses Postganglionic parasympathetic synapses Various sites in CNS Basal nucleus of Meynert Ganglia of visceral motor system
How is ACh made synthesised?
Synthesised in nerve terminals from acetyl CoA and choline
Catalysed by choline acetyltransferase
How is ACh broken down?
hydrolysed by acetylcholinesterase at the synpatic cleft into acetate and choline
Choline is taken up into cholinergic neurons by a high-affinity Na+/choline transporter
What are the 2 types of ACh receptor?
Nicotinic
Muscarinic
What is a nicotinic ACh receptor?
Nonselective cation channels
Generate excitatory postsynaptic responses
Found at ganglion between pre and postganglionic nerve
What is a muscarinic ACh receptor?
Metabotropic
Mediate most of the effects of Ach in the brain
Highly expressed in the striatum
Found at the presynaptic membranes after the postganglionic nerve
Can glutamate cross the BBB?
Nope
What can glutamate be synthesised from?
Glucose
Glutamine
How is glutamate synthesised from glutamine?
Glutamine is released by glial cells
Taken up into presynaptic terminals
Metabolised into glutamate by glutaminase
What happens to glutamate once its been released?
Released glutamate is taken up by glial cells and converted into glutamine
Enzyme - glutamine synthetase
Glutamine is then transported out of glial cells and into nerve terminals
What generate an excitatory response with glutamate?
All ionotropic glutamate receptors (NMDA, AMPA, kainite)
Allow passage of Na+, K+ and Ca2+
What does Ca2+ concentration act as?
A second messenger to activate intracellular signalling cascades
What blocks the NMDA receptor channel when hyperpolarised?
Mg2+
What is required to push Mg2+ out of the NMDA pore?
Depolarisation and glycine
What is the difference is synaptic currents between NMDA and AMPA?
Synpatic currents produced by NMDA receptors are slower and longer-lasting that AMPA/kainate receptors
What does activation of metabotropic glutamate receptors mean?
Leads to inhibition of postsynaptic Ca2+ and Na+ channels
Cause slower postsynaptic responses that can either in crease or decrease the excitability of postsynaptic cells
Where is glycine abundant?
The spinal cord grey matter of the ventral horn
What is GABA formed from?
Glutamate
Where is glycine abundant?
The nigrostriatal system
What catalyses the conversion of glutamate to GABA?
Glutamic acid decarboxylase - found almost exclusively in GABAergic neurons
What is most GABA converted into?
Succinate by GABA transaminase
What are the 3 postsynaptic GABA receptors?
GABAa - ionotropic
GABAb - metabotropic
GABAc - ionotropic
Where can GABA-c receptors be found?
Retina
What happens during ionotropic GABA receptor activation?
GABA binds between the α and β subunits, causing Cl- ions to flow into the neuron, leading to a decreased chance of action potential (hyperpolarisation)
What happens when GABA-b receptors are activated?
Due to the activation of K+ channels and inhibition of Ca2+ channels which tends to hyperpolarise postsynaptic cells
What is dopamine?
A catecholamine dervied from dopa
Produced by action of DOPA decarboxylase on L-DOPA
What happens once dopamine is released?
Once released, dopamine acts exclusively by activating G-protein-coupled receptors.
Most dopamine receptor subtypes act by either activating or inhibiting adenylyl cyclase.
Activation and inhibition of these receptors generally contribute to complex behaviours, depending on the receptor subtype being activated.
