CASE 7 - Parkinson’s Disease Flashcards
list the main components of the basal ganglia
- striatum = caudate nucleus + putamen
- globus pallidus (external and internal)
- substantia nigra (pars compata and pars reticularis)
- nucleus accumbens
- subthalamic nucleus
what makes up the input section of the basal ganglia?
caudate nucleus and putamen (neostriatum)
what makes up the output part of the basal ganglia?
GPi and SNr
what is the putamen separated from the GPe by?
the lateral medullary lamina
what are GPi and GPe separated by?
medial medullary lamina
what makes up the lentiform nucleus?
putamen + globus pallidus
what is the thin bundle of grey matter lateral to the external capsule?
claustrum
what and where is the extreme capsule?
- more lateral to the claustrum
- white matter tracts separating the claustrum from the neocortical insula
the substantia nigra has a dark appearance due to what?
the presence of neuromelanin in the SNc
what is inferior to the thalamus and right above the substantia nigra?
subthalamic nucleus (STN)
what does the internal capsule separate?
the putamen and caudate nucleus
what is the dorsal striatum primarily involved in?
control over conscious motor movements and executive functions
dorsal striatum vs central striatum
dorsal = caudate nucleus + putamen
central = nucleus accumbens + olfactory tubercle
what is the central striatum responsible for?
limbic functions of reward and aversion
dorsolateral vs ventromedial basal ganglia
dorsolateral = motor
ventromedial = limbic
what are the classical cardinal symptoms of PD?
bradykinesia, resting tremor, postural instability, shuffling gait
what is PD a result of?
neurodegeneration of the SNc dopaminergic neurons
what is the nigrostriatal pathway?
a bilateral dopaminergic pathway in the brain that connects the SNc in the midbrain with the dorsal striatum in the forebrain
why is movement in PD not smooth, coordinated or controlled?
- relative overactivity of indirect pathway and suppression of direct pathway
- excessive inhibitory output to thalamus
- thalamus inhibition causes suppression of thalamocortical-cortico-spinal pathway
- hence movement not smooth, coordinated or controlled
upon initiation of voluntary movements, frontal lobes send an ______ signal via ______ to the _______
excitatory signal via glutamate to the striatum
in the direct pathway, the neurones in the striatum send an inhibitory signal where?
GPi and SNr
summarise the direct pathway
how is dopamine involved in the direct pathway?
- neurons in the SNc secrete dopamine onto specific cells in the striatum and activates the excitatory D1 receptors
- overall effect is that dopamine activates the striatum, which inhibits the GPi
- the GPi is then unable to inhibit the thalamus so therefore the thalamus can stimulate the cortex
in the indirect pathway, what does the striatum do?
sends an inhibitory signal via GABA to GPe
what does the GPe normally do?
inhibit the STN
summarise the indirect pathway
how is dopamine involved in the indirect pathway?
- DA is secreted by the SNc and binds to D2 receptors in the striatum
- D2 receptors are inhibitory
- striatal neurones therefore decrease their inhibitory message to the GPe
- GPe can therefore carry out its normal job and suppress the excitatory actions of the STN on GPi (GPe inhibits its internal counterpart)
- less excitation to GPi = less inhibition of thalamus = more excitation of cortex = increased movement
how does dopamine cause increased movement?
by activating the direct pathway and and inhibiting the indirect pathway
describe dopamine structure
catecholamine — catechol moiety (benzene ring + 2 OH side groups) + amine side chain
what are catecholamine derived from?
tyrosine amino acid
how is dopamine made?
tyrosine —> L-DOPA —> Dopamine
- tyrosine hydroxylase
- L-aromatic amino acid decarboxylase (LAADC)
where is dopamine synthesised?
cytoplasm of presynaptic terminals
what happens to DA after it is synthesised?
loaded into synaptic vesicles by vesicular monoamine transporter (VMAT)
what 2 major enzymes are involved in the breakdown of DA?
monoamine oxidase (MOA) and catechol O-methyltransferase (COMT)
for eye movements, the ________ topically suppresses the ________. this inhibiton prevents distracting visual input from triggering unwanted saccadic eye movements. when a saccade is desired, the ______ inhibits a region of the ________. this removes the brakes from a region of the __________, releasing the selected saccade.
for eye movements, the substantia nigra topically suppresses the superior colliculus. this inhibiton prevents distracting visual input from triggering unwanted saccadic eye movements. when a saccade is desired, the striatum inhibits a region of the substantia nigra. this removes the brakes from a region of the superior colliculus, releasing the selected saccade.
what neuropeptides are used in the 2 pathways?
direct = substance P dynorphin
indirect = enkephalin
blood supply of the cerebellum?
superior cerebellar, anterior inferior and posterior inferior cerebellar arteries
what is the posterior inferior cerebellar artery a branch of?
vertebral artery
where is the cerebellum?
- occupies most of posterior fossa
- largest part of hindbrain
- attached to dorsal aspect of brainstem by cerebellar peduncles (superior to midbrain, middle to pons, inferior to medulla)
what does the cerebellum do?
controls maintenance of balance, influences posture and muscle tone, and coordinates movement
- coordinates balance and movement
- concerned with which muslces need to be activated to achieve a particular movement, timing, force
- integrates info from the cerebral cortex (via pons) and peripheral sense organs
- sends output to brainstem nuclei and cerebral cortex
the cerebellum sends output to the brainstem nuclei and cerebral cortex via what?
thalamus
input connections to cerebellum?
- spinocerebellar tracts
- vestibular nuclei
- cerebral cortex (via pontine nuclei)
where does output come from in the cerebellum?
deep cerebellar nuclei
where does output from the cerebellum go?
to brainstem (reticular, vestibular, red nuclei) and thalamus
which nuclei are the functional divisions of the cerebellum associated with?
archicerebellum — associated with fastigial nuclei
paleocerebellum — associated with globose and emboliform nuclei
neocerebellum — associated with dentate nuclei
which part of the cerebellum receives input from vestibular nuclei in the brainstem and is primarily concerned with regulation of movements underlying posture and equilibrium, and vestibulo-ocular reflexes?
archicerebellum
what is the only part of the cerebellum to receive input directly from the spinal cord?
paleocerebellum
which part of the cerebellum projects to the red nucleus?
paleocerebellum
what is the paleocerebellum concerned with?
muscle tone and posture
the superior cerebelalr peduncle decussates in the ______ at the level of what?
decussates in the midbrain at the level of the inferior colliculi
where does the neocerebellum project?
ventral lateral nucleus of thalamus
what regulates highly skilled movements of the extremities?
neocerebellum
lateral part vs vermis of paleocerebellum
lateral — movements of distal muscles
vermis — movements of proximal muscles and also regulates eye movements in response to vestibular inputs
what does the superior cerebellar peduncle contain?
- afferents from ventral spinocerebellar tract to paleocerebellum
- carries most output from cerebellum
each cerebellar hemisphere is concerned with what side of the body?
ipsilateral
all output from the cerebellar cortex are carried by what to the deep cerebellar nuclei?
Purkinje cells
the thalamus projects to the motor cortex and influences what?
corticospinal and corticobulbar UMNs
axons from the emboliform and globose nuclei project where and influence UMNs in the what?
- red nucleus
- rubrospinal tract
axons from the fastigial nuclei influence UMNs where?
reticulospinal and vestibulospinal UMNs in the reticular formation and vestibular nuclei
where does visual and auditory info go to in cerebellum?
spinocerebellum (fastigial nucleus)
hypontonia indicates a lesion where in the cerebellum?
paleo/spinocerebellum
failing the finger to nose test indicates a lesion where in the cerebellum?
cerebro/neocerebellum
PARK mutations cause what type of PD?
recessive
mutations in PARK genes affect what?
the function and survival of nerve cells critical for normal movement, balance and coordination
mutations in what cause dominant PD?
SNCA, LRRK2
what is an example of a neurotoxin that wipes out dopaminergic neurones?
MPTP
PD protective factors
- smoking
- coffee
- NSAIDs
- vigourous exercise
PD core clinical features
- bradykinesia
- rigidity
- resting tremor
what is no Lewy bodies in familial early-onset PD associated with?
Parkin mutation
describe Lewy bodies
- occlusion bodies in neurones — damage the neurones, causing degeneration
- main component = a-synuclein
- interfere with dopamine production
- caudo-rostral spread through brain regions through vagus nerve
what are 3 mechanisms of cell death?
- excitotoxicity
- oxidative stress
- apoptosis
what is often the 1st motor symptom?
tremor
what is the tremor like in PD?
- resting tremor whcuh lessens during sleep and when the body part is actively in use
- pin-rolling remor
- begins on one side with a tremor rate of 3 to 7 cycles per second
- absent in around 30% PD patients
- thalamo-cortical-cerebellar loops (modified by basal ganglia activity)
- usually gets worse over time
what is micrographia a result of?
bradykinesia and hypokinesia (loss of momentum/force in movement)
theory behind anosmia?
clumps of a-synuclein in olfactory bulb
when does loss of smell usually occur in PD?
early on
trouble moving/walking, soft voice, decreased facial expressions, trouble swallowing and eating, reduced arm swinging
why do these occur?
- due to bradykinesia
- net output if basal ganglia becomes more inhibitory due to drop in DA — overactivity of indirect pathway
alpha-synuclein proteins form into _____ that accumulate in ______ cells, leading to the degradation and death of the cell
alpha-synuclein proteins form into fibrils that accumulate in dopamine cells, leading to the degradation and death of the cell
constipation in PD?
- loss of DA in GI tract causing the stomach contents to empty into the small intestine too slowly = gastroparesis
why do neurons in PD release too much ACh and what can this cause?
neurons in the corpus striatum release ACh, whose release is normally inhibited by dopamine. In PD, there is not this inhibition, so these neurons release too much ACh.
tremor and rigidity
what are the 2 types of rigidity?
cogwheel and lead pipe
cogwheel vs lead pipe rigidity
—> lead pipe = constant resistance to motion throughout the entire range of movement
—> cogwheel = resistance that stops and starts as the limb is moved through its range of motion
- Cogwheel Rigidity - Refers to a hypertonic state with superimposed ratchet-like jerkiness and is commonly seen in upper extremity movements (e.g., wrist or elbow flexion and extension). The cogwheel type of rigidity is a combination of lead-pipe rigidity with tremor.
- Lead Pipe Rigidity - Refers to hypertonic state throughout the range of motion i.e simultaneous co-contraction of agonists and antagonists and this is reflected in an immediate resistance to a reversal of the direction of movement about a joint.
what are cognitive disturbances linked to?
changes in dopamine handling in basal ganglia loops
what is later dementia linked to?
cortical Lewy body pathology
what is impulse behaviour linked to?
more severe dopaminergic deficit in limbic ventral striatal areas
what causes dyskinesia?
DA level fluctuations in combination with the loss of dopaminergic neurones
what are peak dose dyskinesia and diphasic dyskinesia?
dyskinesia can occur when the level of levodopa in the body is at a maximum, referred to as peak dose dyskinesia, or when the levels of levodopa are rising or falling, referred to as diphasic dyskinesia.
what is a festinating gait?
shuffling gait with a forward stooped posture and asymmetrical arm swing
when is freezing of gait seen in patients?
- approx 30% within 50 years
- 60% after 10 years
rest vs. intention (essential) tremor
- essential (intention) begins when a person begins an action
- resting tremor stops when they begin an intentional tremor
parkinson’s = rest
describe finger tapping
- patient instructed to tap the index finger on the thumb as fast as possible and as big as possible (patient to try to separate the 2 fingers as much as possible before tapping them)
- slowing of speed, loss of amplitude and pauses in finger taps are consistent with bradykinesia
what does 18F-fluorodopa bind to?
vesicles in the brain containing dopamine
what is fluorodopa?
(FDOPA —18F-fluorodopa) is a fluorinated form of L-DOPA that is synthesised fro use as a radiotracer in PET scans
SPECT vs PET
what are MAOA inhibitors conraindicated with?
levodopa
tricyclic antidepressants have what kind of side effects?
extra pyramidal
links with depression and anxiety and PD
- depression is a risk factor for impulse control disorders
- cognitive decline may occur early in the condition and is rarely absent in advanced disease
- depression is very common
- the prevelance of dementia in PD is estimated at 26% to 44% with over 80% developing dementia within 20 years of diagnosis
- depression can exacerbate cognitive impairments in PD< and the frequency of depression is estimated at 25-33%
- depression and anxiety tend to be more frequent during medication if-periods and often improve when the dopaminergic treatment is optimised
- SSRIs frequently used to treat PD patients with depression
- 2/3 of PD patients with motor fluctuations experience anxiety
loss of Ach-producing neurones vs dopamine-producing neurones
loss of acetylcholine-producing neurones is thoguht to account for degeneration in memory and learning, while loss of dopamine-producing neurones is thoguht to account for degeneration in behaviour, cognition, mood, movement, motivation and sleep
what does DBS target?
areas of brain with excessive beta band activity
where are electrodes put in DBS?
in STN or GPi
DBS works best to lessen what?
motor symptoms of stiffness, slowness and tremor
who qualifies for DBS?
parkinson’s for more than 4 years and who get a benefit from medication but have motor complications such as significant “off” periods (when symptoms return because medication isn’t working well)
what is 1st line PD treatment?
levodopa
levodopa vs dopamine
levadopa can cross BBB
precursor to DA
how is levodopa taken?
- very short acting
- taken with food to avoid nausea vomiting
- usual dose around 800mg/24hours in divided doses but get up to this level gradually
- usually given with carbidopa (cobeneldopa), entacapone or benserazide — agents that decrease L-dopa metabolism and thus prolong its half life
side effects of levodopa
dyskinesias, compulsive behaviour, psychosis (direct result of increased DA levels in brain)
describe on-off levodopa effect?
- related to the fluctuating plasma concentration of L-Dopa
- the effect is seen more often the longer the drug has been used. it is also seen in untreated patients
- this leads to occasions where the drug is effective, and periods where it is not effective at all, and the symptoms of PD dramatically return. This usually occurs at the ‘end of dose’ – i.e. in the hours as the drug is wearing off, but before it is time to take the next dos
why does the effectiveness of levodopa gradually decline?
this mainly reflects the natural progression of the disease, but receptor downregulation and other compensatory mechanisms also contribute. the ability of neurones to store dopamine is lost to the therapeutic benefit of levodopa depends increasingly on the continuous formation of extranueronal dopamine
what is co-benledopa?
levodopa + benserazide
describe benserazide
- a peripherally-acting DOPA decarboxylase inhibitor
- combined with levodopa to reduce peripheral side effects
- cannot cross the BBB so doesn’t prevent the effects of levodopa in the brain
describe rasagiline and selegiline
- MAO-B inhibitors
- inhibition of MAO-B protects dopamine from extraneuronal degradation
- MAO-B preferentially metabolises dopamine over NE and 5-HT
- adjunctive to levodopa
- may enhance adverse effects of L-dopa
- no cheese-effect (acute attack of hypertension that can occur in a person taking a MAOI drug who eats cheese due to the interaction of MAOI width tyramine)
what is entacapone?
- COMT inhibitor
- prevents peripheral breakdown of levodopa, allowing more levadopa to reach the brain
what does COMT break down?
DA, NE and adrenaline
what is amantadine?
- NMDAR antagonist
- blocks Glu
- reduces dyskinesias by around 40%
what is neuroleptic malignant syndrome characterised by?
high fever, muscle rigidity, altered mental status, fast or abnormal heart beat, very high or low blood pressure
levodopa vs dopamine agonists
in control of movement by the basal ganglia, which of the following is true for the indirect pathway?
- the thalamus sends excitatory signals to the motor cortex
- the cerebral cortex sends inhibitory projections to the striatum
- the external globus pallidus sends excitatory signals to teh subthalamic nucleus
- the striatum sends inhibitory signals to the internal globus pallidus, which then sends excitatory projections to the thalamus
- the subthalamic nucleus sends excitatory signals to the internal globus pallidus
the subthalamic nucleus sends excitatory signals to the internal globus pallidus
symptoms of Parkinson’s disease do NOT include:
- excessive sweating
- headaches
- shuffling gait
- convergence insufficiency
- facial rigidity
headaches
benserazide inhibits which of the following enzymes to reduce PD symptoms?
- catechol-O-methyltransferase
- tyrosine hydroxylase
- monoamine oxidase A
- dopa-decarboxylase
- monoamine oxidase B
dopa-decarboxylase
which of the following is NOT a risk factor for PD?
- genetics
- exposure to pesticides
- smoking
- age
- sex
smoking
which of the following side effects is commonly associated with L-DOPA treatment?
- excessive salivation
- hypertension
- hypersexuality
- psychosis
- gambling
psychosis
what is the only portion of the basal ganglia to produce Glu?
STN
the caudate and putamen develop from what division of the neural tube?
telencephalon
the substantia nigra develops from what division of the neural tube?
mesencephalon
what is the frequency of a Parkinsonian resting tremor?
4-6 Hz
what gene is associated with early onset PD?
parkin
what is the most common age of onset of PD?
55-65
what is a potential side effect of selegiline?
hypersexuality
what sites are commonly targeted in DBS?
GPi and STN
