Parkinson’s disease

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Parkinson's disease (PD) is a chronic, progressive, hypokinetic, neurodegenerative condition resulting from the loss of the dopamine-containing cells of the substantia nigra in the midbrain.

Age is the single greatest risk factor and it predominantly affects adults over 65 years. However, it may affect individuals aged 21-40 years ol in young-onset Parkinsonism and even those aged under 21 years old with juvenile Parkinsonism.

It is the second most common neurodegenerative disease (after Alzheimer’s) and affects 0.3% of the population. It affects men more commonly than women (3:2).

🦴 Anatomy

The substantia nigra is a structure located in the midbrain and forms a part of the basal nuclei. It is divided into 2 parts:

1. Substantia nigra pars compact (SNc) - this region contains neurons that are responsible for dopamine production. They are crucial for the regulation of voluntary movement.
2. Substantia nigra pars reticulata (SNr) - this region is lateral to the pars compacta and contains inhibitory GABAergic neurons.

Let’s quickly discuss the basal nuclei and control of voluntary movement:

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Basal ganglia and voluntary movement control:

The basal ganglia, also referred to as the basal nuclei, are a set of 6 interconnected subcortical nuclei that control the rate of movement. It forms part of a circuit that receives inputs from the cortex and relays information back to the cortex - ultimately modulating cortical activity.

The nuclei are spread throughout the forebrain and can be divided into 3 sections:

1. Input nuclei - this includes the caudate nucleus and the putamen (which are collectively referred to as the striatum). The nucleus accumbens is located rostrally at the region where the caudate nucleus and putamen meet. It is involved in the reward system and is the interface between motivation and action.
2. Intrinsic nuclei - this includes the globus pallidus externa (GPe), subthalamus, and the SNc. The subthalamus house glutamatergic neurons.
3. Output nuclei - this includes the globus pallidus interna (GPi) and the SNpr.

The basal ganglia are not fully understood but we know they participate in higher order and cognitive aspects of motor control (planning and execution of complex motor movements). It is also involved in the modulation of cognition and emotional responses. It acts as a filter for expression of inappropriate movements.

• Input organisation - the striatum (caudate + putamen) receives inputs from widespread regions of the central nervous system (such as the thalamic nuclei, limbic structures, substantia nigra pars compacta, raphe nuclei and the entire cortex). The primary motor cortex (M1) projects to the putamen with raw motor information, while the association cortices (premotor cortex and supplementary motor area) project to the caudate with preprocessed information.
• Output organisation - the basal nuclei then output to the thalamus (which then outputs to the cortex). Before reaching the thalamus, the basal nuclei modulate the motor control through 2 pathways:
1. Direct pathway

This is an excitatory pathway that stimulates movement through disinhibition of the thalamus, thus allowing it to relay to the cortex.

The cortex excites the striatum through glutamate (excitatory). This then stimulates the release of GABA (inhibitory) onto the GPi and SNr which normally inhibits the thalamus. As the GPi does not inhibit the thalamus, the thalamus is thus “disinhibited” and is able to then stimulate the cortex through glutamate release. The ultimate result is an increase in movement.

2. Indirect pathway - this is an inhibitory pathway that inhibits movement through disinhibition of the subthalamus which stimulates suppression of the thalamus and therefore suppression of the motor cortex.

The cortex excites the striatum through glutamate. This then stimulates the release of GABA onto the GPe which normally is inhibiting the subthalamus. As the GPe is now inhibited, the subthalamus is disinhibited. The subthalamus stimulates the GPi and SNr through glutamate release. This then allows the GPi and SNr to inhibit the thalamus. The thalamus is now unable to stimulate the cortex and ultimately we have a decrease in movement.

The 2 pathways counterbalance each other to prevent hypokinetic and hyperkinetic disorders.

💡 The term disinhibition refers to a reduction of the synaptic inhibition exerted by a GABAergic neuron onto a glutamatergic neuron by using another GABAergic neuron to inhibit the initial GABAergic neuron’s effect (essentially 2 negatives make a positive).

So what about the substantia nigra pars compacta?

The substantia nigra pars compacta projects onto the striatum with dopaminergic neurons. Depending on the type of receptor dopamine works on, it can either increase or decrease adenylate cyclase which increases or decreases the levels of cAMP to either promote or suppress motor activity. Let’s take a look:

• D1 receptors - these are found in the direct pathway. Agonism of the receptor by dopamine increases adenylate cyclase to increase cAMP and this potentiates the direct pathway → increased movement.
• D2 receptors - these are found in the indirect pathway. Agonism of the receptor by dopamine decreases adenylate cyclase to decrease cAMP and this suppresses the indirect pathway → increased movement (remember that the indirect pathway is inhibitory - therefore, by suppressing it we increase movement).

Pathophysiology

The full aetiology of PD is not yet known, but we do know there are genetic predispositions and environmental factors contributing to the disease.

An environmental factor involved in the pathogenesis is MPTP, a neurotoxin which selectively damages dopaminergic neurons in the substantia nigra. MPTP is found in herbicides.

10% of cases, PD are considered inherited in an autosomal dominant or autosomal recessive pattern with one of the following genes being implicated:

1. SNCA - autosomal dominant. Encodes for α-synuclein. α-synuclein is a lipid-binding protein within synaptic terminals that regulates synaptic vesicle trafficking and recycling. When we have impairments in mitochondrial function and also an increase in oxidative stress → we get misfolding and aggregation of alpha-synuclein → Lewy body inclusions. These inclusions are neurotoxic and lead to destruction of the neurons.
2. LRRK2 - autosomal dominant. Encodes for leucine-rich repeat kinase 2 (LRRK2), also known as dardarin. This is the most common cause of dominantly inherited PD. Dardarin is a cytoplasmic kinase. The mutation leads to hyperphosphorylation of targets, contributing to PD development.
3. PRKN - autosomal recessive. Encodes for the parkin protein. This is the most common cause of recessively inherited PD. The parkin protein is part of a complex that enables ubiquitin to move from a ubiquitin carrier to its substrate, allowing for the degradation of misfolded/damaged proteins. So, this mutation results in the lack of degradation and accumulation of misfolded proteins. This mutation may lead to early onset/juvenile parkinsonism.
4. PINK1 - autosomal recessive. Encodes for the PTEN-induced kinase 1 enzyme which activates parkin for mitophagy (mitochondrial degradation).

These mutations, environmental factors, or other mechanisms end up causing oxidative stress → converts dopamine into free radicals & selective substantia nigral damage.

Clinical features

Signs of PD gradually progress over time: The course is usually > 10 years.

Often, PD patients exhibit non-motor symptoms that precede the motor symptoms and worsen with time. Such as:

• Constipation
• Sleep disturbance (such as restless les syndrome) and insomnia
• Mood disorders; depression, apathy, anxiety
• Anosmia (loss of sense of smell)

Motor symptoms:

The classic triad of symptoms (Parkinsonism) is:

• Bradykinesia: movements getting slower and smaller
• Resting tremor: tremor that is worse at rest
• Rigidity: resistance to passive movements

The diagnosis of PD does not depend on the presence of all 3. It necessitates the presence of bradykinesia with one of the other 2 components of the triad.

Other motor symptoms:

• Postural instability (increasing the risk of falls), due to losing the righting reflexes which involves making small movements to regain balance.
• Myerson sign (+ve glabellar reflex): persistent blinking after tapping the area between the eyebrows.
• Signs of dystonia, such as the arm falling down slowly after raising it above the head quickly
• Stooped posture, due to increased tone of the axial muscles

⟁: Parkinsonism TRAPs the patient: Tremor, Rigidity, Akinesia, and Postural instability.

<aside> 🐌 Bradykinesia

Bradykinesia in PD can manifest as follows:

• Micrographia - handwriting that gets smaller and smaller
• Shuffling gait - small steps while walking
• Propulsion: forward-leaning gait with a risk of a patient falling forward
• Festinating gait - rapid frequency of steps to compensate for the small steps and avoid falling
• Freezing: difficulty initiating movement (I.e going from standing still to walking)
• Difficulty in turning around when standing and having to take lots of little steps to turn
• Hypomimia - reduced facial movements and facial expressions

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<aside> 🧂 Tremor

The resting tremor in PD is:

• Asymmetric, and worse on one side
• 4-6 Hz frequency. The frequency of a tremor refers to the number of oscillations or cycles of movement that occur within a specific time frame. This means that the hand (or whichever part has the tremor) shakes back and forth 4-6 times per second.
• Described as a “pill-rolling tremor” due to the appearance of rolling a pill between their fingertips and thumb.
• More noticeable at rest, better on voluntary movement.
• Gets worse when the patient is distracted, or performing a task with the opposite hand. </aside>

<aside> 🤜🏽 Rigidity

This is the resistance to a passive movement of a joint (increased muscle tone). Examples:

• Taking a hand and flexing and extending the arm at the elbow → movement of the forearm in small increments(like little jerks). This is known as cogwheel rigidity.
• Muscle tone should be tested with at least two joints. </aside>

Table: Difference between PD tremor and ET.

Investigations

This is a clinical diagnosis, based on the history, features and physical examination findings.

Diagnosis is further supported/ confirmed by a positive response to dopaminergic medication. An absolute failure to respond to 1-1.5g of levodopa daily almost excludes a diagnosis of idiopathic Parkinson's disease.

We can also consider doing an MRI head or dopamine transporter scan (DAT) in atypical presentations, such as early onset dementia.

NICE guidelines (2017) recommend the UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria:

DDx

If not idiopathic Parkinson's disease, the following can cause parkinsonism:

• Drug-induced e.g. antipsychotics, metoclopramide (domperidone, although belonging to the same family, does not cause these features as it does not cross the BBB)
• Drug-induced parkinsonism has slightly different features to Parkinson's disease:
• Motor symptoms are generally rapid onset and bilateral
• Rigidity and rest tremor are uncommon
• Progressive supranuclear palsy: early gait instability and falls, vertical gaze palsy, prominent axial rigidity
• Multiple system atrophy: very prominent autonomic dysfunction, early postural instability, poor response to levodopa
• Wilson's disease
• Post-encephalitis
• Dementia pugilistica (secondary to chronic head trauma e.g. boxing)
• Toxins: carbon monoxide, MPTP

Management

Once a secure diagnosis of idiopathic Parkinson's disease has been made, the choice of long term treatment is dependent primarily on the effect that the motor symptoms are having on the patient's quality of life.

Management of non-motor symptoms should also be put in place, but won't be discussed now as these are discussed in separate conditions (such as anxiety, constipation, hypotension, etc).

At the end of life, the focus of management should be on symptomatic relief (for example from constipation, pressure, ulcers, breathlessness, secretions, N&V, etc).

PD pharmacotherapy:

<aside> 🔄 Recap

Tyrosine is converted by tyrosine hydroxylase into levodopa (L-Dopa), which is converted by dopamine decarboxylase(DDC) into dopamine.

Dopamine in the synaptic cleft is taken up by monoamine oxidase B (MAO-B), and by Catechol-O-methyltransferase(COMT).

Note that MAO-B metabolises dopamine, but COMT is able to metabolise both dopamine and L-Dopa.

L-Dopa is able to cross the BBB, but dopamine is not.

Pharmacotherapies aim to relieve symptoms by:

• Increasing dopamine production
• Decreasing dopamine breakdown
• Mimicking dopamine

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<aside> <img src="/icons/pill_purple.svg" alt="/icons/pill_purple.svg" width="40px" /> L-Dopa

The administration of L-Dopa → more dopamine production.

L-Dopa is the most commonly used medication in the treatment of PD.

Since L-Dopa can be taken up by central and peripheral neurons, its side effects are:

Peripheral:

• Postural hypotension
• N&V

Nausea can be managed by domperidone, a peripheral D2 antagonist.

Central:

• Hallucinations
• Confusion
• Dyskinesia

This is one of the most disabling side effects of L-Dopa. It causes writhing and uncoordinated movements of the limbs, due to poorly organised dopaminergic control of muscle activity.

• Psychosis

To reduce the peripheral side effects (and increase L-Dopa centrally where need it to be), DDC inhibitors are added. These inhibitors do not cross the BBB, so they only inhibit the conversion of L-Dopa into DA in the periphery:

• Co-careldopa [carbidopa + L-Dopa] AKA sinemet
• Co-beneldopa [benserizide + L-Dopa] AKA madopa

With time, and as the underlying disease progresses, levodopa may become a less effective and patients may report end-of-dose effects, where motor activity progressively declines as the previous dose wears off, and on-off phenomena, which manifest as seemingly random fluctuations in drug effect. It typically takes 2-5 years to develop complete loss of response.

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<aside> <img src="/icons/pill_purple.svg" alt="/icons/pill_purple.svg" width="40px" /> Dopamine agonists

This group aims to mimic dopamine. They have a longer half life than levodopa, but are not as potent and have a higher frequency of getting side effects (which are the same as L-Dopa's).

They are often used in early disease in those without functional impairment, or late in disease when dyskinesias and motor fluctuations secondary to levodopa is a problem.

• Examples include:
• Oral agonists: ropinirole, pramipexole
• Transdermal patches: rotigotine
• Subcutaneous injections: apomorphine

Apomorphine is the most potent dopamine agonist. It works well against motor fluctuations and dyskinesia. Often used late in disease. Beware autoimmune haemolytic anaemia in these patients & regular FBCs and DAT scans should be done.

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<aside> <img src="/icons/pill_purple.svg" alt="/icons/pill_purple.svg" width="40px" /> MAO-B Inhibitors

MAO-B inhibitors work on decreasing the breakdown of dopamine. By inhibiting MAO-B, we increase the amount of available dopamine in the synaptic cleft.

They are often used in combination with levodopa later in disease.

• Examples include: Selegiline, Rasagiline.
• Can cause serotonin syndrome (view here). </aside>

<aside> <img src="/icons/pill_purple.svg" alt="/icons/pill_purple.svg" width="40px" /> COMT Inhibitors

COMT-I's work by inhibiting the breakdown of L-Dopa and dopamine → increasing dopamine levels. They extend the use of levodopa and are useful in the “wearing off” effect in levodopa use.

Examples: entacapone and tolcapone.

• Tolcapone is more potent than entacapone (because it can cross the BBB) and can result in hepatotoxicity. </aside>

<aside> <img src="/icons/pill_purple.svg" alt="/icons/pill_purple.svg" width="40px" /> Amantadine

• It is an antiviral, used against the influenza virus.
• It is thought to increase dopamine release and decrease its reuptake. It might also be a NMDA receptor antagonist.
• Can be used in those suffering from dyskinesia. </aside>

• excessive sleepiness, hallucinations and impulse control disorders

Surgical Management of Parkinson's disease:

Deep Brain Stimulation: typically done by implanting a stimulating device into a target area of the brain, often the thalamus or the subthalamus.

<aside> 🚘 DVLA

The Driver and Vehicle Licensing Agency (DVLA) states that people with a diagnosis of Parkinson's disease must notify the DVLA following diagnosis:.

Generally, the individual can drive if safe to do so. If the individual's condition is disabling and/or there is clinically significant variability in motor function, the licence will be refused or revoked.

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