Pathophysiologically, what's going on in the brain is
the development and deposition of alpha synuclein.
So idiopathic Parkinson's disease
is an alpha synucleinopathy.
And when we think about Parkinsonism,
Parkinsonisms and Parkinsonian conditions,
we have some that are synucleinopathy
and some that are tauopathies.
Let's spend a few minutes
thinking about the synucleinopathies.
Alpha synuclein is a neuronal protein
that regulates synaptic vesicle trafficking,
and neurotransmitter release.
Alpha synuclein is mainly localized at
the presynaptic terminals of the neurons,
but it's also present in other subcellular
compartments, in the cytoplasm and the Golgi complex.
In the alpha-synucleinopathies
we have build up of alpha synuclein.
This starts in the neuronal cytoplasm, where
unfolded monomers of alpha synuclein interact
and aggregate together to form unstable
dimers and oligomers interact even further
to form amyloid fibrils, and you
can see a depiction of those fibrils here
developing and gumming up
normal neural circuitry in the brain.
Further accumulation of these fibrils
results in the development of a Lewy body.
And a lewy body is is an abnormal aggregated
protein that disrupts normal neural function.
Pathophysiologically, why is
alpha-synuclein buildup so bad?
Well, there's two things I want you to
think about that alpha-synuclein does.
And the first is it builds up in neurons and we
see abnormal neural activity as a result of this
byproduct waste product that is
accumulated within the neuron.
In addition, we also
see microglial activation.
And this is the immune mediator within the
brain, the microglia and this activation of microglia
contributes to ongoing damage that occurs in
the neurons and other structures within the brain.
And the result is neurodegeneration,
progressive neurologic dysfunction, decline,
and ultimately atrophy and loss of
key neural structures in these conditions.
So let's think a little bit more about what's
happening on a global scale within the brain
in this alpha-synucleinopathy
and other Parkinsonisms.
We categorize this condition
as an extrapyramidal disorder.
And if we think back to the pyramidal and
extrapyramidal systems, they're different.
They're different in terms of where they
are, and in terms of what patients present with.
The extrapyramidal system
is the basal ganglia system.
It's the caudate, putamen,
globus pallidus internus, externus,
the subthalamic nucleus
and the substantia nigra.
And together that circuitry makes
up the extrapyramidal system.
Problems with the extrapyramidal
system present as Parkinsonisms
with bradykinesia, rigidity, postural
instability, with or without tremor.
That contrast a pyramidal
The pyramidal system is the
upper motor neuron system.
It's the corticospinal and corticobulbar
fibers and dysfunction of the pyramidal system
presents with weakness and spasticity
and increased tone and hyperreflexia.
So disorders are very separate in terms of
those that affect the extrapyramidal system
and the pyramidal system, both in how they
present and how we manage those patients.
So let's look a little bit closer at the key
clinical manifestations of a Parkinsonism.
We're going to start with bradykinesia,
which means reduced movement.
There's less movement, smaller movements, an overall
reduction in the amount of movement of the patient.
This is seen in 80% of idiopathic PD patients.
Patients will have decreased
manual dexterity of the fingers
and we may see reduced finger tapping
or opening and closing of the hands.
This progresses from distally often to proximally,
and we'll see less movement of the entire body.
shuffling of gait can be seen
reduced arm swing can be seen.
Patients will describe difficulty in completing
simple tasks such as tying shoelaces,
buttoning clothes, picking up small objects,
all of their movements will be slowed and small.
And one of the things
we look at is the gait.
And shuffling of gait is one manifestation
of bradykinesia or reduced movement.
Let's talk a little bit about the
second cardinal feature - rigidity.
And this is really important seen in 70 to 80%
of patients with idiopathic Parkinson's disease.
It's described as increased
resistance to passive movements.
So when we evaluate rigidity,
we have the patient relax.
We're looking at passive movement
so we're moving the patient's joint
as opposed to the patient moving
volitionally And we have increase in tone.
Importantly, rigidity and parkinsonism are different
from the spasticity we see from stroke patients.
spasticity is a pyramidal system,
it is velocity and angle dependent.
There's more resistance out on extension and more
resistance, the faster the arm or leg or limb removed.
Rigidity is not clasp-knife spasticity.
It has lead-pipe rigidity.
And so patients who have rigidity
or an extrapyramidal symptom
have increase in tone
throughout the range of movement
and with any ankle or velocity, so
it's not velocity or ankle dependent.
This begins often unilaterally, particularly in
patients with idiopathic Parkinson's disease
and can progress to the
contralateral side, or in some patients,
remaining asymmetric throughout
the course of the disease.
And in some patients, particularly
those with idiopathic Parkinson's disease,
we can see cogwheel rigidity.
cogwheel rigidity is that
combination of rigidity plus tremor.
Patients are very stiff, there's increased tone to
passive movement and on top of that, we have a tremor.
And the result is cog wheeling, or that resistance
and relaxation of passive movement at the same time.
Postural instability is important.
This is one of the most important of those
initial three cardinal symptoms of a Parkinsonism.
It usually occurs in more advanced
stages of idiopathic Parkinson's disease,
and this is defined
clinically using the pull test.
The patient is standing upright, the
examiner stands behind the patient.
And without the patient looking or being
aware, the examiner will pull back the patient,
pull back on their shoulders and
the patient is instructed to remain still.
The patient's, on a normal exam
is for the patient to remain upright.
And an abnormal exam is for the
patient to take multiple steps backwards,
or to fall as a result of the inability to
right oneself using their axial musculature.
And then the last cardinal feature is tremor.
This is not seen in all parkinsonisms, but is
primarily seen in idiopathic Parkinson's disease.
The tremor we see in idiopathic
Parkinson's Disease is a rest tremor
and often described as a pill rolling tremor,
with the appearance of the patient rolling a pill
in between their thumb and index finger.
This is intermittent early in the stages of idiopathic.
It decreases with voluntary actions, so when
patients are moving, we don't see the tremor,
and when their limbs remain
at rest, it is more obvious.
It can involve the hands often initially
or even the legs, lips, jaw and tongue.
And initially in idiopathic Parkinson's
disease, it's often unilateral,
but can progress to bilateral involvement.
And importantly, these four cardinal
features can be seen in any Parkinsonism.
With classic Parkinsonisms, we see
rigidity, bradykinesia, postural instability.
In idiopathic PD, we often also see tremor.
And now let's look at a video of an
example of the pull test being performed.
And here we're going to see
the patient standing upright.
The examiner is placed behind the
patient and instructs them to remain upright.
A pole or force is exerted on the patient's shoulders,
and the patient is instructed to stay upright.
A normal finding is a patient
remaining upright or taking one step.
And patients who take multiple steps
or may fall have a reduction in axial tone,
which is indicative of Parkinsonism.
Now let's look at a video of tremor.
There are a number of different
types of tremor that we can see.
Two of the most common types of tremor are rest
and action or which what is called a kinetic tremor.
The rest tremor that we see is present at
rest when the arms are still or the legs are still
And often will induce this by asking
the patients to rest their arms and legs
and ask them to recite the days of the week
or the months of the year forward or backward
distracting them to
bring out that rest tremor.
That's different from a kinetic or
action tremor which is present with action
To evaluate action or kinetic tremors, we'll have the
patient draw a series of spirals and action movement
and we're looking for the presence of
that tremor during action movement.