Parkinson’s Disease

Dr. Katie Dabrowski, PT, DPT

Parkinson’s disease (PD)+ A progressive neurodegenerative disease – there is a

destruction of specific nerve cells, causing symptoms to worsen over time

+ No known cure, no effective medical treatment to slow orhalt the progression

+ Affects changes in movement (tremor, slowness, and stiffness), as well as many non-motor symptoms

Pathophysiology+ PD is known as an α-synucleinopathy – it is a disease characterized by the

misfolding of a protein called α-synuclein+ This protein is found in the brain, heart, gut, and skin and is proposed to

be involved in the dopamine transport system + In healthy individuals, this protein does not aggregate (clump up); in

pathological individuals, this protein will aggregate and cause fibrils to form – called Lewy bodies – on nerve cells, causing them to be damaged and eventually die

+ This happens in specific regions of the brain and body in PD, causing the characteristic symptoms of the disease, which we will discuss

+ The most affected area of the brain in PD is the substantia nigra, a region of the basal ganglia

Pathophysiology+ The substantia nigra is an area deep in the brain, in the basal

ganglia, that contains a high percentage of dopaminergic neurons

+ Dopamine, produced in the substantia nigra, passes messagesbetween the striatum and the substantia nigra

+ The striatum is another region of the basal ganglia, and is involved in movement and balance

+ So death of dopaminergic neurons in the substantia nigra, characteristic of PD, results in less dopamine passed between the striatum and the substantia nigra, ultimately resulting in disruptions in movement and balance

Quick detour…let’s dive a little deeper into these brain regions and their normal functions

Basal ganglia regions

+ Anatomically, the basal ganglia has different regions:1. Corpus Striatum (Caudate, Putamen, and Globus Pallidus)

2. Subthalamic Nucleus

3. Substantia Nigra (Pars Compacta, Pars Reticulata)

Basic Functions of Regions of the Basal Ganglia+ Putamen (of the striatum) = planning, sequencing of

movement

+ Caudate (of the striatum) = associative learning, cognition

+ Globus pallidus (of the striatum) = inhibitory to the thalamus

+ Substantia nigra = dopamine, reward

+ Subthalamic nuclei = reward circuit

Primary Basal Ganglia Inputs/Outputs+ Most of the input to the basal ganglia comes from different

areas of the cortex:

Input from the cortex à caudate and putamen of the striatum àthroughout the rest of the basal ganglia à thalamus à cortex

*It is important to note that the input from the basal ganglia to the thalamus is inhibitory. We’ll discuss this further.

Basal Ganglia Pathways for Movement Initiation/Termination+ There are two pathways of the BG for initiating or

terminating movement:

+ Direct Pathway: Facilitates movement

+ Indirect Pathway: Inhibits movement

Direct Pathway: Facilitates MovementStriatum à globus pallidus internus (GPi) and substantia nigra à thalamus à cortex

-The striatum has a very strong inhibitory connection to Gpi

-The GPi has an inhibitory connection the thalamus

-The thalamus has an excitatory connection to the cortex

Direct Pathway: Facilitates MovementSo how does this pathway facilitate movement?

The very strong inhibitory connection between the striatum and the GPi results in TOO MUCH inhibition of the GPi, which means the GPican’t do its job to inhibit the thalamus. This means MORE INFORMATION will travel to the cortex via the excitatory connection between the thalamus and cortex

THIS RESULTS IN MOVEMENT!

Direct Pathway: Facilitates Movement…explained another wayThink of it like a double negative: Cells in the striatum have inhibitory connections with cells in the GPi. The GPi cells in turn have inhibitory connections with cells in the thalamus. So firing neurons in the GPi results in inhibiting the thalamus, making the thalamus less likely to excite the cortex. So in the case of the direct pathway, when the cells in the striatum fire, they inhibit the activity of the GPi. This inhibition releases the thalamic neurons from inhibition (it disinhibits the thalamic neurons), allowing them to fire and excite the cortex. So it’s like a double negative that becomes a positive (negative from striatum to GPi and negative from GPi to thalamus = double negative = positive from thalamus to cortex).

Indirect Pathway: Inhibits Movement+ Striatum à globus pallidus externus (GPe) à Subthalamic nucleus

à globus pallidus internus (GPi) à substantia nigra à thalamus àcortex

-The striatum has an inhibitory connection to the GPe-GPe has inhibitory connection to subthalamic nucleus-Subthalamic nucleus has excitatory connection to GPi and substantia nigra -GPi and substantia nigra have inhibitory connections to thalamus-Thalamus has excitatory connection to the cortex

Indirect Pathway: Inhibits Movement+ So how does this inhibit movement?

The striatum inhibits the GPe a lot, therefore the GPe will not be able to inhibit the subthalamic nucleus like it is supposed to. This results in the excitatory connection between the subthalamic nucleus and the GPi and the substantia nigra

Indirect Pathway: Inhibits Movement…explained another way+ Cells in the striatum have inhibitory connections to the GPe.

The GPe has inhibitory connections to the subthalamic nucleus, which in turn has excitatory connections to the GPi[remember this is the only excitatory connection besides cortex � striatum and thalamus � cortex]. Remember from before, GPi has inhibitory connections to the thalamus. Sowith excitation from the subthalamus to the GPi, the already inhibitory connection to the thalamus is enhanced, and this results in inhibition from that thalamus to the cortex.

So what happens in Parkinson’s disease?+ Age of onset: 40-50 years old

+ Degeneration of dopamine cells in in substantia nigra pars compacta (SNc)

+ Results in reduction in dopamine production

+ Combination of genetic and environmental factors

Looking back at the pathophysiology+ Loss of dopamine-producing cells in SNc

+ SNc will not inhibit the GPi and putamen enough, resulting in TOO much thalamic inhibition, resulting in decreased cortical excitation

+ This results in rigidity, bradykinesia (Slow movement), postural instability, and resting tremors

Looking back at the pathophysiologyThe SNc does not inhibit the GPi enough – therefore, the GPi is abnormally active, resulting in too much inhibition of the thalamus. Therefore, the motor cortex is very inhibited and is less able to execute the motor plans for the individual.

Parkinson’s favors the indirect pathway discussed above.

Pathophysiology, simplified:

+ The BG typically exerts inhibitory control over the motor systems, preventing activation at inappropriate times

+ When a particular action is required, inhibition of the BGis reduced, allowing activation of voluntary movement (direct pathway)

Pathophysiology, simplified:

+ Dopamine acts to facilitate the release of that inhibition’

+ High levels of dopamine produce voluntary motor activity

+ Low levels of dopamine reduce voluntary motor activity

+ Dopamine reduction in PD results in reduced motoroutput

Clinical Characteristics

+ Akinesia and bradykinesia

+ Complex, sequential, and simultaneous movements are particularly impaired

+ Difficulty with transitions in between movements

+ Freezing of gait (getting ‘stuck’ in movements)

+ Postural instability

Clinical Characteristics+ Rigidity

Form of hypertonia

Resistance to passive movement affecting BOTH sides of the joint equally

+ Resting Tremor+ Masked face

Reduced facial expressions

+ Monotonous speechReflection of bradykinesia

+ Festinating gaitIncreased cadence with decreased step length

+ Cognitive functionsMay be impaired (due to dopamine decrease)

Clinical Characteristics

+ Numbness, tingling (paresthesias)

+ Dysphagia

+ Olfactory dysfunction

+ Pain

+ Cognitive dysfunction

+ Depression

+ Anxiety

+ Social withdrawal

+ Autonomic dysfunction

Treatment+ Dopamine Agonists

+ Generally first choice with younger onset patients to delay or decrease risk of developing dyskinesia

+Generally after 3 years, levodopa will need to be added to control progression of parkinsonian symptoms

+ Administered by injection (Apomorphine) or patch (Rotigotine)

Treatment+ Levodihydroxyphenylalanine (Levodopa)

Generally first choice with older onset patients (less side effects, predictable benefits)+ Converted by dopa-decarboxylase (DDC) to dopamine once transported

through blood brain barrier

Combined with Carbidopa (Sinemet) to prevent DDC from converting L-dopa in peripheral tissues

Administered orally, three or more doses throughout waking hours+ Carbidopa/levodopa (i.e., 10/100 mg)

After use > 5 years, 50% patients developed dyskinesia+ Younger onset > older onset

Treatment+ Deep Brain Stimulation

+ Surgical procedure used to treat several disabling neurological symptomsTremor, rigidity, stiffness, slowed movement, and walking problems

Essential tremor, dystonia

+ Neurosurgeon uses MRI or CT scanning to identify and locate the exact target within the brain for surgical intervention.Some surgeons may use microelectrode recording to more precisely identify the area of the brain that will be stimulated+ Subthalamic nucleus, Globus pallidus internus, or Thalamus