Case 7 Flashcards
what is the major efferent neurotransmitter of the peripheral nervous system?
Ach - found at the neuromuscular junction, preganglionic autonomic synapses, and postganglionic parasympathetic synapses.
• ACh serves as a transmitter at synapses in the ganglia of the visceral motor system, and at a variety of sites within the CNS, especially in the basal nucleus of Meynert.
how and where is acetylcholine synthesised?
Acetylcholine is synthesized in nerve terminals from the precursors acetyl coenzyme A and choline, in a reaction catalyzed by choline acetyltransferase (CAT).
how and where is ACh hydrolysed? what takes up choline?
Ach is hydrolyzed by acetylcholinesterase (AChE) at the synaptic cleft into acetate & choline. Choline is taken up into cholinergic neurons by a high-affinity Na+/choline transporter.
what are the two types of ACh receptors?
- Nicotinic ACh receptor (nAChR) are nonselective cation channels that generate excitatory postsynaptic responses – found at the ganglion between pre- and postganglionic nerve.
- Muscarinic ACh receptors (mAChRs) are metabotropic and mediate most of the effects of ACh in brain. Muscarinic ACh receptors are highly expressed in the striatum and various other forebrain regions – found at the presynaptic membranes after the postganglionic nerve.
The main difference between the two is their MOA, one uses Ions (Nicotinic) and one uses G-Proteins (Muscarinic). Nicotinic receptors are all exciatory, while Muscarinic receptors can be both excitatory and inhibitory depending on the subtype. Another difference being where they are found on the body. (Sympathetic vs Parasympathetic Nervous System)
You find Muscarinic Receptors in the brain, heart, smooth muscle, or in the Parasympathetic nervous system. While Nicotinic Receptors are found in the Sympathetic nervous system, Muscarinic receptors are not. This is the crucial difference.
most excitatory neurones in the CNS are what?
glutamatergic
what happens with elevated concentrations of extracellular glutamate, released as a result of neural injury?
toxic to neurones
does glutamate cross the blood-brain barrier? what does this mean?
no
- therefore it must be synthesised in neurones from local precursors, either from glucose or glutamine
- glutamine is released by glial cells
- once released, glutamine is taken up into presynaptic terminals and metaboliesd to glutamate by the mitochondrial enzyme glutaminase
what happens to glutamate in the synaptic cleft?
- it’s taken up by glial cells and converted into glutamine by the enzyme glutamine synthetase
- glutamine is then transported out of the glial cells and into nerve terminals
what do all the ionotropic glutamate receptors generate? give examples for the receptors
(NMDA, AMPA, and kainate)
generate excitatory postsynaptic responses allowing the passage of Na+, K+ and Ca2+.
EPSPs produced by NMDA receptors can increase the concentration of what within the postsynaptic neurone?
the Ca2+ concentration change can then act as a second messenger to activate intracellular signaling cascades.
at hyperpolarised membrane potentials, what blocks the pore of the NMDA receptor channel? what changes this?
• At hyperpolarized membrane potentials, Mg2+ blocks the pore of the NMDA receptor channel.
• Depolarization, however, pushes Mg2+ out of the pore, allowing other cations to flow.
The opening of this receptor requires glycine
most glutamatergic synapses possess what receptors?
both AMPA and NMDA
The synaptic currents produced by NMDA receptors are slower and longer-lasting than the those produced by AMPA/kainate receptors.
what does activation of metabotropic glutamate receptors lead to?
• Metabotropic glutamate receptor (mGluRs) - Activation of many of these receptors leads to inhibition of postsynaptic Ca2+ and Na+ channels.
mGluRs cause slower postsynaptic responses that can either increase or decrease the excitability of postsynaptic cells.
what do most inhibitory synapses in the brain and spinal cord use as neurotransmitters?
γ-aminobutyric acid (GABA) or glycine
what is GABA formed from? and how?
glutamate
The enzyme glutamic acid decarboxylase (GAD), which is found almost exclusively in GABAergic neurons, catalyzes the conversion of glutamate to GABA.
in which system is GABA abundant?
the nigrostriatal system
what is most GABA eventually converted to? what does inhibition of GABA breakdown cause?
succinate by GABA transaminase
• Inhibition of GABA breakdown causes a rise in tissue GABA content and an increase in the activity of inhibitory neurons.
what are the different types of GABA receptors? how do each work?
- GABAA and GABAC (GABAc is found in the retina) receptors are ionotropic receptors.
- GABAB receptors are metabotropic receptors.
- The ionotropic GABA receptors are usually inhibitory because their associated channels are permeable to Cl-.
- GABA binds to a binding pocket between the α and β subunits, causing Cl- ions to flow into the neuron, leading to a decreased chance of action potential (hyperpolarisation).
- GABAB receptors are inhibitory due to the activation of K+ channels and inhibition of Ca2+ channels which tends to hyperpolarize postsynaptic cells.
where is glycine abundant?
in the spinal cord grey matter of the ventral horn
what is dopamine?
a catecholamine derived from dopa that functions as a neurotransmitter
what does dopamine act on?
acts on specific dopamine receptors and also on adrenoreceptors throughout the body, especially in the limbic system and extrapyramidal system of the brain as well as the arteries of the heart.
describe how dopamine is produced, released, take up, and broken down
- Dopamine is produced by the action of DOPA decarboxlyase on L-DOPA.
- Following its synthesis in the cytoplasm of presynaptic terminals, dopamine is loaded into synaptic vesicles via a vesicular monoamine transporter (VMAT).
- Dopamine action in the synaptic cleft is terminated by reuptake of dopamine into nerve terminals or surrounding glial cells by a Na+-dependent dopamine transporter, termed DAT.
- The two major enzymes involved in the catabolism of dopamine are monoamine oxidase (MAO) and catechol O-methyltransferase (COMT).
- Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT.
how does cocaine produce its psychotrpoic effect?
by binding to and inhibiting DAT, yielding a net increase in dopamine release
what gives rise to the dopaminergic system?
two structures of the mid brain give rise to the system:
- substantia nigra
- ventral tegmental area
what does substantia nigra mean? why called this?
This is latin for “black substance”, reflecting the fact that parts of this structure appear darker than neighbouring areas due to high levels of neuromelanin in dopaminergic neurons.
what is the nigrostriatal pathway?
arises mainly from the substantia nigra pars compacta and projects to the caudate and putamen (collectively known as striatum). This pathway serves as the primary input into the basal ganglia system.
what does dysfunction of the nigrostriatal pathway produce?
movement disorders such as Parkinson’s disease
what results in Parkinson’s disease?
degeneration of the dopamine-containing cells/neurones in the substantia nigra
what are two pathways arising from the ventral tegmental area? describe each.
- mesolimbic pathway
- mesocortical pathway
- Mesolimbic Pathway – arises mainly from the ventral tegmental area and projects to limbic structures (ventral striatum - nucleus accumbens). This pathway plays a major role in reward circuitry and addiction.
- Mesocortical Pathway – arises mainly from the ventral tegmental area and projects to the prefrontal cortex. This pathway is involved in working memory and attentional aspects of motor initiation.
what does dopamine act on when released? what happens after that?
- 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.
what are the basal ganglia?
large and functionally diverse set of nuclei that lie deep within the cerebral hemispheres
what does the basal ganglia facilitate and suppress?
The basal ganglia facilitate the initiation of motor programs that express movement and the suppression of competing motor programs that would otherwise interfere with the expression of sensory-drive or goal directed behaviour.
which nuclei in the basal ganglia are concerned with motor movement?
- corpus striatum (caudate nucleus and putamen)
- globus pallidus
how do the basal ganglia influence movement?
The basal ganglia do not project directly to either the local circuit or lower motor neurons; instead they influence movement by regulating the activity of the upper motor neurons.
what structures are closely related with the motor functions of the basal ganglia?
substantia nigra (base of midbrain) and the subthalamic nucleus (ventral thalamus)
what do the basal ganglia along with other structures form? what is this imporant for?
The basal ganglia, along with the substantia nigra and the subthalamic nucleus form a ‘loop’. The neurons of this loop respond in anticipation of and during movements, and their effects on upper motor neurons are required for the normal course of voluntary movements.
what happens when one of the components of the loop is compromised?
the patient cannot switch smoothly between commands that initiate a movement and those that terminate the movement
the disordered movements that result from a compromisation of one of the components in the loop can be understood as a consequence of what?
abnormal upper motor neurone activity in the absence of the supervisory control normally provided by the basal ganglia
what are the largest source of input into the basal ganglia? describe it.
- the corticostriatal pathways from the cortex
- these travel through the internal capsule to reach the caudate and putamen directly
- they consist of multiple parallel pathways serving different functions
- this segregation is maintained in the structures that receive projections from the striatum, and in the pathways that project from the basal ganglia to other brain regions (?)
what are the only cortical areas that don’t project to the corpus striatum?
the primary visual and primary auditory cortices
how are cortical projections to basal ganglia mapped?
they are topographically mapped within rostrocaudal bands
what are the destinations of the incoming axons from the cortex to the basal ganglia?
the dendrites of medium spiny neurones in the corpus striatum
what neurotransmitter does most cortical input to the striatum use?
glutamate - it’s excitatory
what are the main sources of output from the basal ganglia?
The axons arising from the medium spiny neurons converge on neurons in the globus pallidus and the substantia nigra pars reticulata, the main sources of output from the basal ganglia complex
what is the substantia nigra divided up into?
pars compacta and pars reticulata
what are medium spiny cells?
the cells in the basal ganglia that receive input from the brain
what are the circuits in the basal ganglia? what neurotransmitters do they use?
Cerebral cortex»_space;> medium spiny cells
Synaptic transmission occurs via glutamate.
Interneurons»_space;> medium spiny cells
Synaptic transmission occurs via GABA or Acetylcholine.
Substantia nigra pars compacta»_space;> medium spiny cells
Synaptic transmission occurs via dopamine.
what must happen for the medium spiny neurones to become active?
- The medium spiny neurons must simultaneously receive many excitatory inputs from cortical and nigral neurons to become active.
- As a result the medium spiny neurons are usually silent.
what are the two types of interneurons in the basal ganglia?
- The interneurons are of two types: (1) GABAnergic (2) Acetylcholine.
- The interneurons that are smaller in size are GABAnergic; those that are larger release Acetylcholine.
dopamine and glutamate interact to do what?
modulate synaptic strength
- Long-term potentiation
- Glutamate activates receptors and causes excitation of neurones, but dopamine receptors are then modulating the amount of signal
- Glutamate is driving the activity of the neurones but dopamine is affecting the eventual output of the neurones
what does the voluntary control of movement consist of?
direct pathway and indirect pathway
direct pathway for the voluntary control of movement
- what used for
- what doesn’t involve
- what effect does activation of the primary motor cortex and thalamus have
- The direct pathway is used in order to stimulate muscle movement.
- This pathway does not involve the Globus Pallidus externus (Dpe).
- In this pathway, activation of the Primary Motor Cortex and the Thalamus have excitatory effects.
describe the direct pathway
- Signals from the primary motor cortex are sent to the putamen (glutamate).
- This causes an increase in the (inhibitory) function of the putamen.
- Signals are sent from the putamen to the GPi (GABA).
- Due to the inhibitory function of the putamen, there is a decrease in the (inhibitory) function of GPi.
- Signals are sent from the GPi to the thalamus (GABA).
- Due to the decrease in the inhibitory function of the GPi, there will be an increase in the excitatory function of the thalamus.
- The thalamus sends signals to primary motor cortex, forming a feedback loop (glutamate).
- This causes the primary motor cortex to stimulate muscle movement.
indirect pathway of the voluntary control of movement
- what’s it used for
- what does it involve
- The indirect pathway is used in order to inhibit muscle movement.
- This pathway involves the Globus Pallidus externus (Dpe).
describe the indirect pathway
- Signals from the primary motor cortex are sent to the putamen (glutamate).
- This causes an increase in the (inhibitory) function of the putamen.
- Signals are sent from the putamen to the GPe (GABA).
- Due to the inhibitory function of the putamen, there is a decrease in the (inhibitory) function of GPe.
- The GPe also projects to the subthalamic nucleus (GABA) and GPi (GABA).
- This causes an increased excitatory function of the subthalamic nucleus .
- The subthalamic nucleus has an excitatory function and so excites the GPi (glutamate).
- As the GPi has an inhibitory effect, there is an increase in this inhibitory effect of the GPi due to the stimulation by the subthalamic nucleus and the direct stimulation from GPe.
- Signals are sent from the GPi to the thalamus (GABA).
- Due to the increase in the inhibitory function of the GPi, there will be an decrease in the excitatory function of the thalamus.
- The thalamus sends signals to primary motor cortex, forming a feedback loop (glutamate).
- This causes the primary motor cortex to inhibit muscle movement.
what stimulates muscle movement? how?
- When the primary motor cortex is ready to simulate muscle movement, it sends signals to the substantia nigra compacta.
- The substantia nigra compacta stimulates the direct pathway to cause muscle movement AND at the same time it inhibits the indirect pathway.
• Normally:
Activation of D1 receptor stimulates the direct pathway.
Activation of the D1 receptor causes an increase in dynorphin, thus causing stimulation of the direct pathway.
Activation of D2 receptor inhibits the indirect pathway.
Activation of the D2 receptor causes a decrease in enkephalin, thus causing inhibition of the indirect pathway.
how are eye movements controlled in the basal ganglia?
- Signals are sent from the corpus striatum to the substantia nigra pars reticulate.
- The axons from substantia nigra pars reticulata synapse on upper motor neurons in the superior colliculus that command eye movements, without an intervening relay in the thalamus.
describe neurotransmission in the direct and indirect pathways
• Striatal projection neurons for both pathways are primarily inhibitory spiny neurons, which contain the neurotransmitter GABA.
• In the direct pathway, spiny striatal neurons project to GPi (and to the substantia nigra pars reticulata) and contain substance P in addition to GABA.
Output neurons from the GPi and substantia nigra pars reticulata to the thalamus are also inhibitory and contain GABA.
• In the indirect pathway, striatal neurons project to GPe and contain the inhibitory neurotransmitter GABA, plus encephalin (via D2R dopamine receptors).
Output neurons of the GPe, in turn, send inhibitory GABAergic projections to the subthalamic nucleus.
Excitatory neurons in the subthalamic nucleus containing glutamate then project to the GPi and to the substantia nigra pars reticulata.
• As in the direct pathway, outputs from these nuclei to the thalamus are inhibitory and are mediated by GABAergic neurotransmission.
the internal segment of the globus pallidus sends outputs to the thalamus through which pathways?
The ansa lenticularis is named for the looping course it takes ventrally under the internal capsule before passing dorsally to reach the thalamus.
The lenticular fasciculus penetrates straight through the internal capsule. It then pass dorsal to the subthalamic nucleus and ventral to the zona incerta before turning superiorly and laterally to enter the thalamus.
the fibres of the ansa lenticularis and lecticular fasciculus join together to form what?
the thalamic fasciculus, which enters the thalamus
what does the subthalamic fasciculus do?
it carries fibres of the indirect pathway from the GPe to the subthalamic nucleus, and from the subthalamic nucleus to the GPi
what is the cerebellum dividied into?
3 lobes: anterior lobe, posterior lobe, and flocculonodular lobe
what does the flocculonodular lobe do?
it functions with the vestibular system in controlling body equilibrium
what is each gyrus on the cerebellum called?
a folium
how can the cerebellum be divided?
- Cerebrocerebellum – regulation of highly skilled movements for the extremities.
- Vestibulocerebellum – comprises the flocculus and the nodulus.
The vestibulocerebellum receives input from the vestibular nuclei in the brainstem and is primarily concerned with the regulation of movements underlying posture and equilibrium. - Spinocerebellum – occupies the median and paramedian zone of the cerebellar hemispheres and is the only part that receives input directly from the spinal cord.
The lateral part of the spinocerebellum is primarily concerned with movements of distal muscles, such as the relatively gross movements of the limbs in walking.
The vermis, is primarily concerned with movements of proximal muscles, and also regulates eye movements in response to vestibular inputs.
what carries outputs from the cerebellum?
the superior cerebellar peduncle mainly
at what level does the superior cerebellar peduncle decussate?
in the midbrain at the level of the inferior colliculi
what carries input to the cerebellum?
the middle cerebellar peduncle and inferior cerebellar peduncle mainly
what are the deep cerebellar nuclei?
Dentate nucleus – Receives input from the lateral cerebellar hemispheres.
Interposed Nucleus – made up of emboliform nucleus and the globose nucleus. They receive input from the intermediate cerebellar hemisphere.
Fastigial nucleus – Receives input from the vermis and a small part of the flocculus. Most fibres leaving the inferior vermis and flocculi project to the vestibular nuclei.
inputs to the cerebellum from the cerebrum:
- what are the different sources of input
- what is the largest source of input? what is the major destination?
The cerebral cortex (primary motor cortex and the premotor cortex) is by far the largest source of inputs to the cerebellum, and the major destination of these inputs is the cerebrocerebellum.
Primary and secondary somatic sensory cortices of the anterior parietal lobe.
Secondary visual regions of the posterior parietal lobe.
where do most of these cortical pathways relay before entering the cerebellum? what happens here? what is the significance of this?
in the pontine nuclei
- the pontine nulcei in turn give rise to the transverse projections that cross the midline and form the middle cerebellar peduncle
- thus relaying these cortical signals to the contralateral cerebellar hemisphere
- thus signals derived from one cerebral hemisphere are received and processed by neural circuits in the opposite cerebellar hemisphere
inputs to the cerebellum from the periphery (?):
- what projects to the vestibulocerebellum
- what projects to the spinocerellum
- what do these inputs together provide the cerebllum with
Vestibular axons from the CN VIII and axons from the vestibular nuclei in the medulla project to the vestibulocerebellum.
Relay neurons in the dorsal nucleus of Clarke in the spinal cord also send their axons to the spinocerebellum. (Dorsal nucleus of Clarke – a group of relay neurons innervated by proprioceptive axons from the periphery).
• The vestibular and spinal inputs provide the cerebellum with information from the labyrinth in the ear, from muscle spindles, and from other mechanoreceptors that monitor the position and motion of the body.
where does the entire cerebellum receive modulatory inputs from? what does this provide?
the inferior olive and the locus ceruleus in the brain stem
- these nuclei participate in the learning and memory functions served by the cerebellar circuitry
what are the cerebellar input pathways? describe each one.
• Afferent information about limb movements is conveyed to the cerebellum by the dorsal spinocerebellar tract for the lower extremity and by the cuneocerebellar tract for the upper extremity.
These pathways provide rapid feedback to the cerebellum about ongoing movements, allowing fine adjustments to be made.
• Information about activity of spinal cord interneurons (a reflection of the amount of activity in descending pathways) is carried by the ventral spinocerebellar tract for the lower extremity and by the rostral spinocerebellar tract for the upper extremity.
spinocerebellar tract divided into four subdivisions:
- dorsal (posterior) spinocerebellar tract
- ventral (anterior) spinocerebellar tract
- cuneocerebellar tract
- rostral spinocerebellar tract
Dorsal Spinocerebellar Tract
• This conveys afferent information about limb movements for the lower extremity.
• Large, myelinated axons of primary sensory neurons carrying proprioceptive, touch, and pressure sensation from the lower extremities and trunk enter via the dorsal roots and ascend in the gracile fasciculus.
• Some of these fibres form synapses in the nucleus dorsalis of Clark.
• Fibres arising from the nucleus dorsalis of Clark ascend ipsilaterally in the dorsal spinocerebellar tract.
• These fibres give rise to mossy fibres that travel to the ipsilateral cerebellar cortex via the inferior cerebellar peduncle.
Cuneocerebellar Tract
• This conveys afferent information about limb movements for the upper extremity.
• Fibres from the upper extremities enter the cuneate fasciculus and ascend ipsilaterally to synapse in the external cuneate nucleus, located in the medulla, just lateral to the cuneate nucleus.
• From the external cuneate nucleus, cuneocerebellar fibres ascend in the inferior cerebellar peduncle to the ipsilateral cerebellum.
Ventral Spinocerebellar Tracts
• This conveys information about activity of spinal cord interneurons for the lower extremity.
• It arises from spinal border cells, spinal cord intermediate zone.
• Axons from these cells cross over in the ventral commissure of the spinal cord to ascend in the ventral spinocerebellar tract.
• The majority of these fibres then join the superior cerebellar peduncle and cross over a second time, to reach the cerebellum ipsilateral to the side where the pathway began.
Rostral Spinocerebellar Tract
• This conveys information about activity of spinal cord interneurons for the upper extremity.
• It enters the cerebellum through both the inferior and superior cerebellar peduncles.
each cerebellar hemisphere is concerned with which side of the body? and therefore what must happen at the cerebellar peduncles when efferent nerve fibres leave the cerebellum to ascend to the cortex?
the ipsilateral side
the efferent nerve fibres must decussate
describe the pathway of output from the cerebellum to the motor cortex. and what is influenced?
- All outputs from the cerebellum are carried by Purkinje cells to the deep cerebellar nuclei or vestibular nuclei.
- Axons from the dentate, fastigial, and interposed nuclei exit in the superior cerebellar peduncle, cross the midline in the midbrain, and terminate in the ventral lateral nucleus of the thalamus.
- The thalamus projects to the motor cortex and influences corticospinal and corticobulbar upper motor neurons.
- Axons from the interposed nuclei also project to the red nucleus and influence upper motor neurons in the rubrospinal tract.
- Axons from the fastigial nuclei influence reticulospinal and vestibulospinal upper motor neurons in the reticular formation and vestibular nuclei.
what is the cerebellum’s role with motor movement? what is neuronal activity for this controlled by? how does firing frequency change? therefore what do lesions in the cerebellum cause?
• The cerebellum monitors and regulates motor behaviour.
• As a result, neuronal activity in the cerebellum changes continually during the course of a movement.
• This is activity is controlled by the Purkinje and the deep cerebellar nuclear cells.
• Both are tonically active at rest and change their frequency of firing as movements occur.
• Changes in the firing frequency of the cells respond selectively to various aspects of movement:
Therefore, due to lesions in the cerebellum, patients find it difficult to produce smooth, well-coordinated movement – cerebellar ataxia.
the cerebellum contributes to error reduction in which systems?
• The cerebellum contributes to the motor error reduction in the oculomotor system:
This is done when a small part of the tendon of the lateral rectus is cut which weakens horizontal eye movement.
The nervous system corrects the error in the saccades made by the weak eye by increasing the gain in the saccade motor system.
Lesions in the vermis of the spinocerebellum eliminate this ability to reduce the motor error
• The cerebellum also contributes to error reduction in the vestibule-ocular reflex system:
If the cerebellum is damaged or removed, the ability of the VOR to adapt to the new conditions is lost.
what is Parkinson’s Disease?
a disease that is characterised by (rest) tremor, rigidity, bradykinesia and postural instability (gait impairment?) - known as cardinal features of the disease
what is PD associated with (cause)?
degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in the underproduction of L-DOPA
what is Parkinsonism?
a clinical picture characterised by tremor, rigidity, slowness of movement, and postural instability (late)
what is the epidemiology of PD?
- PD is the second commonest neurodegenerative disease.
- Prevalence rate = 1.5/1000 in the UK.
- PD affects men and women of all races, all occupations, and all countries.
- The mean age of onset is about 60 years.
- The frequency of PD increases with aging.
- Epidemiologic studies suggest increased risk with exposure to pesticides, rural living, and drinking well water and reduced risk with cigarette smoking and caffeine.
what are the signs and symptoms of PD?
• Cardinal Signs – rest tremor, rigidity, bradykinesia and postural instability/gait impairment
• Writing becomes small (micrographia)
- Patient has an impassive face.
• Additional features can include freezing of gait, postural instability, speech difficulty, autonomic disturbances (gastrointestinal disturbances, sexual dysfunction), sensory alterations, mood disorders, sleep dysfunction, cognitive impairment, and dementia, all known as nondopaminergic features because they do not fully respond to dopaminergic therapy.
what is used to image the brain dopamine system? what does it show?
- PET or SPECT
- shows reduced uptake of striatal dopaminergic markers, particularly in the posterior putamen
what mutations are associated with PD? environmental factors?
- Mutations of the LRRK2 gene are responsible for 1% of typical sporadic cases of the disease.
- Mutations in the parkin gene should be considered in patients with disease onset prior to 40 years.
- Mutations in the SNCA gene cause problems in α-synuclein.
- Genetics
- monogenic forms of PD
- recessive e.g. parkin, dominant e.g. SNCA, LRRK2
- dysfunction in a number of cellular pathways
- helps us understand causes of sporadic PD
how does the loss of dopamine correspond to symptoms time wise? - at what point to symptoms appear?
Gradual loss of dopamine occurs over several years, with symptoms of PD appearing only when the striatal dopamine content has fallen to 20-40% of normal.
which symptom is most clearly related to dopamine deficiency?
hypokinesia - which occurs immediately and invariably
what causes rigidity and tremor?
more complex neurochemical disturbances of other transmitters as well as dopamine
what are two secondary consequences following damage to the nigrostriatal tract?
- A hyperactivity of the remaining dopaminergic neurons, which show an increased rate of transmitter turnover.
- An increase in the number of dopamine receptors, which produces a state of denervation hypersensitivity.
what are the initial symptoms of PD? where is it more prominent?
- Initial symptoms – tremor, slowness, stiffness of limbs and joints, aching joints.
- Idiopathic PD is almost always initially more prominent on one side.
tremor
- what like at rest
- what happens with action/sleep
Characteristic 4-6Hz pill-rolling tremor at rest – typically decreases or stops with action/sleep.
what is rigidity?
what is plastic rigidity?
- Rigidity – stiffness develops throughout movement and is equal in opposing muscle groups. This lead pipe-like increase in tone (plastic rigidity) is usually more marked on one side and present in the neck and axial muscles.
- Plastic Rigidity – is more easily felt when a joint is moved slowly and gently; tone increases when the opposite arm moves actively. When stiffness occurs with tremor, smooth lead pipe rigidity is broken up into a jerky resistance to passive movement – cogwheeling.
what is leadpipe rigidity? what is cogwheel rigidity?
Cogwheel rigidity and leadpipe rigidity are two types identified with Parkinson’s disease:
- Leadpipe rigidity is sustained resistance to passive movement throughout the whole range of motion, with no fluctuations.
- Cogwheel rigidity is jerky resistance to passive movement as muscles tense and relax. (thought to be due to underlying tremor)
what is akinesia? how is this presented?
- difficulty initiating movement
- there is a characteristic decrease in spontaneous blink rate and in facial expression
- speech is poorly articulated and the voice quiet and monotonous
- eating and swallowing become increasingly difficult
what postural and gait changes take place?
- Stooping is characteristic
- Gait becomes hurrying (festinant) and shuffling with poor arm swinging
- The posture has forward flexion, immobility and lack of animation
- Balance deteriorates, but despite this the gait retains a narrow base
- Falls, toppling like a falling tree, are common in later stages
- The diminished ability to make reflex postural adjustments that maintain balance can be disabling and results in a characteristic parkinsonian gait
what happens to speech with PD?
- Pronunciation is initially a monotone and progresses to tremulous slurring dysarthria, the result of akinesia, tremor and rigidity
- Eventually, speech may be lost (anarthria)
what are the cognitive changes in PD?
Cognitive decline may occur early in the condition and is rarely absent in advanced disease. Depression is common.
other features of PD
- is there sensory loss
- reflexes
- plantar response
Other Features:
- There is no sensory loss
- The reflexes are brisk – their asymmetry follows the increase in tone.
- The plantar responses remain flexor.
what is the aetiology of PD? how is familial early-onset PD distinguishable from sporadic PD?
- Most PD cases occur sporadically (90%) and are of unknown cause.
- Environmental factors likely play the more important role in patients older than 50 years, with genetic factors being more important in younger patients.
- Environmental factors
- toxins e.g. MPTP, paraquat
- possibility of spread of toxic/infective agents from gut/olfactory system?
- About 10% of cases are familial in origin.
- Familial early-onset Parkinson’s disease associated with mutations in the parkin enzyme is distinguished from sporadic Parkinson’s disease by lack of Lewy bodies.
what is the pathogenesis of cell death?
Oxidative stress Intracellular calcium accumulation with Exocitotoxicity Inflammation Mitochondrial dysfunction (apoptosis) Proteolytic stress
• Whatever the mechanism, cell death appears by way of a signal-mediated apoptotic or “suicidal” process.
protein aggregation
- link to PD
- what causes it
- how are proteins normally cleared
- what causes PD - familial and sporadic
- The most significant of these mechanisms appear to be protein misfolding and aggregation and mitochondrial dysfunction.
- Parkinson’s Disease is characterised by Lewy Bodies and Lewy Neurites, which are composed of misfolded and aggregated proteins.
- Protein aggregation could result from either increased formation (mutations in α–synuclein) or impaired clearance of proteins.
- Proteins are normally cleared by the ubiquitin proteasome system or the autophagy/lysosome pathway
• Parkinson’s Disease – The protein clearance pathways are defective in patients with sporadic PD, and α-synuclein is a prominent component of Lewy bodies.
Mutations in parkin and UCH-L1 are causative in other cases of familial PD.
Mitochondrial dysfunction has also been implicated in familial PD.
describe the pathophysiology of PD
- Parkinson’s disease is caused by the loss of the nigrostriatal dopaminergic neurons.
- The normal effects of the compacta input to the striatum are excitation of the direct pathway and inhibition of the indirect pathway.
- In contrast, when the compacta cells are destroyed, as occurs in Parkinson’s disease, the inhibitory outflow of the basal ganglia is abnormally high, and thalamic activation of upper motor neurons in the motor cortex is therefore less likely to occur.
- This reduces the activation of cortical motor systems, and the development of parkinsonian features.
• Normally:
Activation of D1 receptor stimulates the direct pathway.
Activation of the D1 receptor causes an increase in dynorphin, thus causing stimulation of the direct pathway.
Activation of D2 receptor inhibits the indirect pathway.
Activation of the D2 receptor causes a decrease in enkephalin, thus causing inhibition of the indirect pathway.
• Parkinsons:
Less activation of D1 receptors:
Less activation means that there will be a decrease in dynorphin, thus causing a decrease in the stimulation of the direct pathway.
Less activation of D2 receptors:
Less activation means that there will be an increase in enkephalin, thus causing a decrease in the inhibition of the indirect pathway.
PET
- what does it stand for
- what is it
- what is detected
- give examples
- what assumption is it based on
• This is a nuclear medicine imagining technique that produces a 3D image/map of functional processes in the body.
• The system detects pairs of gamma-rays that are emitted indirectly by a positron emitting radionuclide, which is introduced to the body on a biologically active molecule.
• An example of this is:
18F-fluorodopa in which the radionuclide is introduced in dopamine - In a condition such as Parkinson’s Disease a PET using the above radiotracer would show a decrease in the dopamine levels in the substantia nigra and associated areas.
18F-fluorodeoxyglucose (FDG) in which the radionuclide is introduced in glucose.
This is used to measure metabolic activity and is useful for catching cancer metastasis.
• PET neuroimaging is based on the assumption that areas of high radioactivity are associated with brain activity.
SPECT
- what does it stand for
- how does it work
- how compare to PET
- It is performed by using a gamma camera to acquire multiple 2D images, also known as projections, from different angles.
- A computer is then used to convert these projections into a 3-D dataset.
- This can then be manipulated to show thin slices along any chosen axis of the body. This is similar to a PET.
- SPECT imaging is much cheaper than PET imaging but it provides a lower resolution image.
- It is also easier to perform because the radioisotope used for SPECT is more readily available and has a longer half-life. The short half-lives of the radioisotopes used in PET imaging means that it has to be made and then delivered straight to the scanning site.
how effective is treatment for PD?
- Treatment does not reverse the morphologic changed or arrest the progress of the disease.
- With progression of the disease, drug therapy tends to become less effective and symptoms become more difficult to manage.
what drugs are used to treat PD?
- Levodopa
- Dopamine Agonists
- MAO-B Inhibitors
what surgery can be used to treat PD?
bilateral subthalamic nucleus (STN) or globus pallidus interna (GPi) stimulation may be used
what is co-beneldopa?
combination of two drugs:
- levodopa
- benserazide
levodopa
- what is it
- how well is it absorbed
- what happens to it
- how long-acting
- how effective
Levodopa (L-DOPA)
• This is a precursor of dopamine.
• It is well absorbed from the small intestine (active transport), although much of it is inactivated by MAO in the wall of the intestine.
• A small percentage of each levodopa dose crosses the blood-brain-barrier and is decarboxylated to dopamine.
• This newly formed dopamine is then available to stimulate dopaminergic receptors, thus compensating for the depleted supply or endogenous dopamine.
- Levodopa is short-acting.
- As time progresses, the effectiveness of levodopa gradually declines.
- It is likely, that the loss of effectiveness of levodopa mainly reflects the natural progression of the disease, but receptor downregulation and other compensatory mechanisms also contribute.
- Overall, levodopa increases the life expectancy of PD patients.
benserazide
- what is it
- what is the point of it
- Benserazide is 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 are the unwanted effects of Levodopa?
There are two main types of unwanted effect:
Involuntary writhing movements (dyskinesia).
Occur at the time of the peak therapeutic effect, and the margin between the beneficial and the dyskinetic effect becomes progressively narrower.
Levodopa is short acting, and the fluctuating plasma concentration of the drug may favour the development of dyskinesias, as longer-acting dopamine agonists are less problematic in this regard.
Rapid fluctuations in clinical state.
Hypokinesia and rigidity may suddenly worsen for anything from a few minutes to a few hours, and then improve again.
The “on-off” phenomenon. As with the dyskinesias, the problem seems to reflect the fluctuating plasma concentration of levodopa, and it is suggested that as the disease advances, the ability of neurons to store dopamine is lost, so the therapeutic benefit of levodopa depends increasingly on the continuous formation of extraneuronal dopamine, which requires a continuous supply of levodopa.
what is an example of a monoamine oxidase-B inhibitor?
Selegiline
Selegiline
- what is it
- what does it do
- what is it most effective treatment for PD
Selegiline is a selective 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 are different types of quality of life (QoL) scale?
• Generic or Illness specific
Generic – Nottingham Health Profile - EUROQOL- EQ5D
Illness specific - Arthritis Impact Measurement Scale (AIMS).
EUROQOL – EQ-5D
- Self-care
- Usual activities
- Pain/discomfort
- Anxiety/depression
• Standardised or Individualised
Standardised - assumes consensus – Barthel index
Individualised - each individual has own definition and criteria for QoL – SEIQoL – (Semi structured interview to select 5 most important domains).
SEIQOL
- Semi structured interview to select 5 most important domains
- Evaluates own life on a line ‘worst’ to ‘best life imaginable’
- Prioritise (weight) each domain
- Calculate index
• Uni-dimensional or Multidimensional
Uni-dimensional – focuses on one particular aspect of health.
Multidimensional – assesses health in the broadest sense. - SF-36
SF-36
- mental health
- physical functioning
- pain
- social functioning
- energy
when is a scale:
- reliable
- valid
- sensitive
- Reliability - A scale is reliable if it measures consistently over time and between people. e.g. test-retest reliability
- Validity - A scale is valid if it measures what its suppose to measure. e.g. criterion validity
- Sensitivity – The scale has to be sensitive to change.
what is emotion?
- A mental state that arises spontaneously rather than through conscious effort and is often accompanied by physiological changes
what is classic Palvovian conditioning? what is fear conditioning? what involved?
Classic Palvovian conditioning:
- CS response is taken to reflect emotional state
- Play a bell before getting fed, dog starts to drool when it just hears the bell
Fear conditioning
- Lesions from the amygdala down abolish fear conditioning completely
- Amygdala may be a key site for fear conditioning
what is effect of bilateral amygdala lesion?
In humans (extremely rare)
- Curiosity overcoming fear
- Impaired recognition of emotional expressions
- Impaired recognition of fear from movie stills
- Generalises to other (especially negative) emotions – not good at recognising anger, sadness
what are the different types of long and short term memory? how do they work?
Long-term
Declarative (explicit) -> episodic (events) or -> semantic (facts)
Implicit -> procedural (skills) or -> priming or -> conditioning
Short-term
Sensory
Working memory
SHORT-TERM MEMORY - Memory for ‘nonsense syllables’ - Memory for number strings -digit span (remembering phone numbers) 7 (plus or minus 2)
PRIMACY (BEGINNING) AND RECENCY (END) EFFECTS
- Last first and last one or two
what is anterograde and retrograde amnesia?
Anterograde amnesia is a loss of the ability to create new memories after the event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact.
Retrograde amnesia (RA) is a loss of memory-access to events that occurred, or information that was learned, before an injury or the onset of a disease.
can you see axons on imaging?
no - can potentially see nerve roots however
what is used to measure neurotransmitters?
PET or SPECT
what’s the positives and negatives of CT and MRI scanning for structural imaging?
CT (microwave meal curry)
- Can see through the other end
- Quick
- Cheap
- Convenient
- Involves radiation – avoid children, pregnant women
- Poor quality
MRI (Michelin star restaurant curry)
- More traumatic – long dark tunnel, really loud
- Slow
- Expensive
- Bit more effort
- No radiation
- But does use quite strong magnetism – don’t put people with loose metal fragments in their bodies in MRI
- High quality
Increasingly in neurology we use MRI over CT
However, normally CT for seeing acutely clotted blood e.g. stroke
what is bright white on a CT scan?
- Bone
- Freshly clotted blood
what do you use to scan if you are interested in the fine details of someone’s nervous system?
If interested in the fine detail of someone’s nervous system, like subtle details of inflammation then you need MRI, not CT scanning
what is used for functional imaging - positives and negatives?
SPECT (a bit like CT) - Gamma emitting radioisotope - Cheap - Convenient - Poor spatial resolution PET (a bit like MRI) - Positron emitting radioisotopes - Expensive - Bit more effort - Good spatial resolution
what are the uses for PET?
OTHER USES FOR PET (other than metabolism?)
- Neurotransmitter
- Pathological proteins
- Neuroinflammation
- Red on scan shows where there’s [18F]-Dopa uptake – areas lacking with Parkinson’s disease – little dopamine activity in striatum
- Imaging not currently used clinically in PD – don’t need it to diagnose, just used for research
what separates the caudate and putamen?
the internal capsule
what can cause hypokinetic and hyperkinetic movement disorders?
basal ganglia dysfunction
what is the input region of the basal ganglia?
striatum
what neurones does the striatum consist of?
- Medium spiny neurones
- 96% striatal neurones
- GABAergic (inhibitory) +_ neuropeptides
- they influence movement by projecting to other areas of the basal ganglia
- Interneurons
- GABAergic (inhibitory)
- Cholinergic (large aspiny neurones)
- don’t project anywhere, but they modulate the activity of other neurones
what does striatal input consist of?
- Corticostriatal pathway
- glutamatergic
- input from whole cerebral cortex
- Nigrostriatal pathway
- dopaminergic
- from substantia nigra pars compacta (where dopamine is synthesised) (pars compacta is a portion of the substantia nigra – formed by dopaminergic neurons and located medial to pars reticulata)
what are the output regions of the basal ganglia?
Medial globus pallidus and substantia nigra pars reticulata are the output pathways of the basal ganglia – they change the functions and determine how much is going on
describe basal ganglia organisation - in terms of pathways
VL thalamus (glutamate) -> cerebral cortex (glutamate) -> striatum (GABA) (+ SNpc (dopamine))
- > GPI (GABA) -> STN (glutamate) -> GPm/SNpr -> brainstem, spinal cord
- > GPm/SNpr (GABA) -> brainstem, spinal cord
what are the important elements in direct and indirect pathway?
Direct pathway - D1 receptors (dopamine 1) - Dynorphin precursor (PPE-B) - Increased adenylyl cyclase -> increased cAMP Indirect pathway - D2 receptors - Enkephalin precursor (PPE-A)
(both D1 and D2 are G-protein coupled receptors – they have opposite effects though)
what’s the difference between tonic dopamine release and phasic dopamine release?
Tonic dopamine release (constant background low level dopamine release) -> low synaptic and extrasynaptic levels -> preferential D2R activation (high affinity receptors) -> action inhibition ‘no-go’ – long-term depression
Phasic dopamine release (spike in dopamine) -> preferential D1R activation -> motor initiation – long-term potentiation
what are the different basal ganglia pathways?
- Direct pathway – facilitation of desired movements
- Indirect pathway – inhibition of unwanted movements
- Parallel loops subserving different functions (motor circuit, associative circuit, limbic circuit)
- Dorsolateral (motor areas) to ventromedial (limbic areas) gradient in terms of function
Decreasing number of neurones as you go down:
- Cerebral cortex
- Striatum
- Pallidum/substantia nigra
- Thalamus
describe the effect of the basal ganglia in parkinsonism
- Loss of dopamine means less excitation
- Which leads to reduced activity in direct pathway
- Reduction in diamorphine – peptide neurotransmitter contained within that pathway
- Decreased indirect pathway means decreased inhibition
- So direct pathway is underactive and indirect pathway is over active
- When you get a loss of dopamine, you get opposite effects on both pathways
overview of pathophysiology in parkinsonism
- Relative overactivity of indirect pathway
- Suppression of movement
- reduction in voluntary movement (bradykinesia)
- rigidity
- Impaired motor learning (loss of LTP – long-term potentiation)
- Subthalamic overactivity
- lesion of STN alleviates experimental parkinsonism
- effects of lesion surgery
what are the behavioural impairments in PD due to?
Cognitive disturbances:
- Linked to changes in dopamine handling in basal ganglia loops
- Later dementia related to cortical Lewy body pathology
Impulsive behaviour:
- Pathological gambling, hypersexuality, compulsive eating
- Linked to more severe dopaminergic deficit in ventral (limbic) striatal areas
Depression, anxiety:
- Related to monoamine cell loss in brainstem
- Dopamine agonists may improve depression in PD
what is the main component of lewy bodies?
alpha-synuclein
how is PD diagnosed?
clincial diagnosis:
- Bradykinesia (obligatory) + one of:
- rigdity
- rest tremor
- postural instability
- Unilateral onset and persistent asymmetry
- Good levodopa response >5 years
- Clinical course >10 years
what are non-motor features of PD?
- Cognitive impairment
- Visual hallucinations
- Mood disorders
- Olfactory deficit
- Pain
- Sleep disorders
- Orthostasis
- Constipation, urine and erectile dysfunction
what are possible pre-motor features of PD?
- REM sleep behaviour disorder
- Anosmia (lack of sense of smell)
- Constipation
- Depression
- Pain
what causes bradykinesia, rigidity and tremor?
BRADYKINESIA
- Increased inhibitory output to central pattern generators in brainstem
- Increased inhibitory output to thalamus and motor cortex
- Abnormal 20 Hz (beta band) oscillations in basal ganglia circuit
RIDIGITY
- Increased muscle tone
- More obvious during slow movements (cf spasticity)
- Peripheral
- reduced inhibition from type Ib fibres
- overactive type II fibres
- increased activity due to peripheral stimulation
- Central
- altered activity in GABA and Ach interneurons
- altered inhibition in indirect pathway
- increased responsiveness of STN/GPi firing to peripheral stimulation
TREMOR
- Absent in around 30% PD
- Less response to dopaminergic drugs
- Not just basal ganglia output
- Thalamo-cortical-cerebellar loops – modified by basal ganglia activity
- Non-dopaminergic pathways e.g. 5-HT ?
how does levodopa compare to dopamine agonists?
Levodopa:
- Better motor improvement in short term
- Reduced freezing of gait
- More dyskinesia, possibly in long term
Dopamine agonists:
- Less dyskinesia and longer latency to dyskinesia
- More adverse effects – nausea, postural hypotension, somnolence
- Impulse control disorders
- Withdrawal problems
what are the motor complications in PD treatment? what are the mechanisms?
MOTOR COMPLICATIONS IN PD
- Motor complications in PD
- wearing-off and motor fluctuations
- L-dopa-induced dyskinesia
- Occur in 50% after 4-6 years treatment
- young age, disease severity associated
- related to disease and treatment duration
- genetic factors
MECHANISMS OF MOTOR COMPLICATIONS
- Pulsatile dopaminergic stimulation
- Abnormal handling of dopamine by 5-HT neurones
- Abnormal synaptic plasticity
- Dopamine receptor agonist treatment delays dyskinesia onset
what are the impulse control disorders in PD? what are the risk factors?
IMPULSE CONTROL DISORDERS
- Prevalence 13.6% in dominion study
- Pathological gambling
- Hypersexuality
- Compulsive shopping
- Binge eating
Risk factors:
- Dopamine agonist use > high dose levodopa
- Smoking, male
- Young-onset PD
- Depression
- Novelty-seeking behaviour
- Family history gambling, alcoholism
Impulse control disorders (ICD) are frequent side effects of dopamine replacement therapy (DRT) used in Parkinson’s disease (PD)
what is QALY? what are guidelines?
QALY – QUALITY ADJUSTED LIFE YEARS
Definition: A measure of the state of health of a person in terms of length of life, are adjusted to reflex the quality of life – one QALY is equal to 1 year of life in perfect health
- Estimate the number of years of life remaining for a patient following a treatment/intervention THEN weighting each year with a quality-of-life score (on a 0 to 1 scale)
- Often measured in terms of the person’s ability to carry out the activities of daily life, and freedom from pain and mental disturbance
At present, NICE’s guidelines for treatment (2010):
- Less than £20,000 per QALY is considered to be clearly cost-effective
- £20,000 – 30,000 per QALY = other sorts of benefits or considerations must be evident
- More than £30,000 per QALY, a strong case needs to be made for the technology to be recommended
what is pallidotomy?
Pallidotomy = procedure whereby a tiny electrical probe is placed in the globus pallidus internus (one of the basal nuclei of the brain), which is then heated to 80C for 60 seconds, to destroy a small area of brain cells
- Alternative to deep brain stimulation for the treatment of involuntary movements – often problem in people with PD
- Pallidotomy -> improvement of parkinsonism
