Parkinson's Disease

What is Parkinson’s disease?

• slow, progressive condition

• prognosis is likely to be impaired as the disease progresses inside the body before it can be diagnosed.

• first described as “the shaking palsy” by Dr. James Parkinson in 1817.

• Parkinson’s Disease is a progressive disorder of the CNS with both motor and non motor symptoms. 

The 1st identification of PD for many patients is:

shaking tremor

• It is the second most common neurodegenerative disorder (what is the #1 disorder _________ ?).

Alzheimer’s

Is PD a neurochemical or a neurodegenerative disorder?

• both are correct

• __% of patients have idiopathic (spontaneous) PD

• Genetic forms less than __%; Other causes include environmental toxins, and industrial chemicals

78%
10%

Idiopathic

no known cause

Two clinical subgroups for PD:

(1) PIGD phenotype (postural instability gait disorder)

(2) TD phenotype (tremor dominant)

*both are movement based findings

• both show a cardinal sign

• likely that one of these two features will be a dominant feature

PD affects parts of the brain that _________ ___________ ____________.

directs voluntary movement

PD affects _% of the population under 65 years of age

Only ____% under 50.

2%

5-10%

____ - ____ x more in males than females

1.2-1.5

Incidence _________ dramatically with increasing age

increases

• <10/100,000 under 50 years old

• 300/100,000 over 80 years old

• With an aging population, both the prevalence and incidence of PD are expected to increase by more than 30% by 2030. 

PD risk factors

• Age

• Heredity: Having a close relative with Parkinson's disease increases the chances, risks are still small unless you have many relatives in your family.

• Gender: Men are more likely to develop PD than women.

• Exposure to toxins: Ongoing exposure to herbicides and pesticides.

Protective factors

• vigorous exercise (breaking a sweat, breathing hard)

• Caffeine (stimulatory effect?) - coffee or tea

• Cigarette smoking (less neurodegeneration)

• non-steroidal anti inflammatory drug use (aspirin, ibuprofen)

What part of the brain is involved?

The Basal Ganglia (BG)

The Basal Ganglia (BG)

• The basal ganglia is made up of large subcortical (deep) structures that are interconnected and interposed between the cortex and the thalamus. 

  • There are also connections to the frontal cortex (via the thalamus), indirectly the cerebellum and brainstem. 

  • The BG is actively involved in almost all types of movements (including postural responses, spontaneously occurring movements, and voluntary movements). 

Direct & Indirect Motor Control

plan for an action starts in cortex → must communicate to basal ganglia before the message is sent down.

If the basal ganglia is affected, so are a lot of other things!

The Basal Ganglia diagram

Caudate and Putamen work together (we group them into the corpus striatum)

• 
  

Where is dopamine found in the brain?

Substantia Nigra

BG and Dopamine

• Our motor pattern, thoughts and behaviors, and memory processes are all initiated through the cerebral cortex.

• Multiple sections of the cortex send off projections to the striatum (caudate and putamen). 

  • Dopamine is produced in the substantia nigra, and is used to increase the efficiency or decrease the effect of cortical input to the striatum.

  • makes it as efficient as possible for a movement to occur.

• Through long-term potentiation and long-term depression, dopamine may be involved in the neural mechanism of _________

habit learning

• Habits are quick and instant → happens with the use of dopamine beacuse it has been done so many times

• Also meaning that depletion of dopamine in the striatum impairs the learning of new movement sequences.

• This is why PD patients have a hard time learning new patterns and movements

Dopamine

• Dopamine goes from the striatum to the internal globus pallidus and the external globus pallidus. 

  • The external globus pallidus sends inhibitory input to the internal globus pallidus.

• The primary basal ganglia output comes from the internal globus pallidus, leading to the Thalamus, which then completed the feedback loop back to the motor cortex.  

Dopamine makes the _______ process nice and smooth

striatum

Where does the cerebral cortex end?

The Internal Pallidus

→ by the time the information gets here, the action should be fine tuned.

What does the basal ganglia do?

The basal Ganglia is inhibitory and acts as a brake on the motor pattern generators in the cerebral cortex

movement interactions between BG and dopamine

• The interaction among these pathways allows for a planned movement to be executed, while competing movements are prevented. 

  • It increases precision without altering the power necessary to perform the activity.

Parkinson’s development

• The signs and symptoms of Parkinson’s are neurochemical in origin. (they lack dopamine)

  • The pathologic hallmark is the degeneration of the substantia nigra, thereby losing its ability to produce dopamine. 

    
    

A depletion of ___% to ___% of the dopamine is estimated to occur before clinical signs of disease are noted. 

70%-80%

Parkinson’s research

• Despite significant research in this area, many observations of cause of PD are correlative in nature and a precise process has not been identified.

There are many possible triggers for the programmed cell death, with some overlap of degeneration that is similar to the processes seen in dementia:

• Protein misfolding, aggregation and toxicity

• Mitochondrial dysfunction

• Neuroinflammation (NSAIDs may be helpful)

NSAID’s

Nonsteroidal anti-inflammatory drugs

Parkinson’s development

1. Neurons with cell bodies in SN and axons that travel to striatum produce neurotransmitter called ‘dopamine’

2. Dopamine: modulates balance between excitatory & inhibitory neural pathways

3. PD clinical features result from degeneration of Nigrostriatal pathway

how dopamine regulates

1. Striatum (caudate & putamen) receives input from “Nigrostriatal pathway” in purple

   
   

2. “Nigrostriatal pathway”: neurons with cell bodies in SN and axons that travel to striatum: produce neurotransmitter called ‘dopamine’

   • reduces activity

   
   

3. Dopamine modulates balance between excitatory (cholinergic) & inhibitory (GABA) neural pathways (less dopamine causes less inhibition)

How does a tremor happen?

too much acetylcholine (excitatory) and no dopamine to balance it out

Clinical Features:

• with 30-60% loss of nigrostriatal neurons you get:

  • Imbalance between excitatory neurotransmitters & inhibiting dopamine neurotransmitters

• relative excess of acetylcholine produces dyskinesia & rigidity

Parkinson’s development

1. Striatum receives input from the cerebral cortex

2. Striatum also receives input form SN

   “Nigrostriatal pathway” Get gradual denervation of striatum

3. The output from internal pallidus to thalamus completes feedback loop back to motor cortex.

When dopamine stimulation is decreased or withdrawn, the overall effect is…

increased inhibition of input from the internal pallidus into the thalamus.

When you inhibit the thalamus…

• decrease the ability of the thalamus to send excitatory input back to the cortex. 

The ultimate outcome:

• less activity in the cortex, resulting in slowed movement and less power generated through the musculoskeletal system. 

  • This explains the contrasting presentations in PD:

Excessive excitation

• the relationship of the substantia nigra and the striatum (caudate and putamen)

Excessive inhibition

• the influence of internal pallidus, to thalamus, and ultimately the cerebral cortex 

In PD, ypu will have ___________ and _________ at the same time

Excessive excitation and excessive inhibition

*cardinal symptom

Parkinson’s summary

• Imbalance between excitatory and inhibitory mechanisms

Key pathologic feature:

• excessive loss of dopaminergic neurons in the substantia nigra

If overall effect is increased inhibitory input to thalamus, what does this mean for cortex?

It means ultimate outcome of PD disease is less activity in cortex (slowed movement and less power)

Why does PD happen?

• We don’t know. 

• There are currently no blood or laboratory tests to diagnose nongenetic cases of Parkinson's disease.

  • Diagnosis is based on a person's medical history and a neurological examination. 

  • this could change very soon…

What does FOG stand for?

Freezing of Gait

4 Characteristic (cardinal) signs in PD

1. Rigidity 

2. Bradykinesia (slowed movement)

• Akinesia (inability to move)

3. Tremor

4. Postural instability

Cardinal

• signs that stand out the most and are looked for first in terms of the condition

Rigidity

• Due to increased resting muscle activity

• Not spasticity

• Is a lesion/defect in the basal ganglia (such as parkinson’s)

Q1. What might someone with PD develop, because of increased resting muscle activity?

• Decreased ROM - contracture formation

Q2. How might increased resting muscle activity affect fatigue?

Never truly at rest - markedly affects fatigue

Bradykinesia

• Failure of the mechanism that programs movement patterns

• Defect in the voluntary production of smooth motions at different speeds

• Hypokinesia

• Akinesia

Hypokinesia

• Decreased frequency of or absence of associated movements (e.g. micrographia, arm swing)

• Parkinson’s walk = no arm swing

Akinesia

• Inability to initiate or execute movement (hypomimia, freezing of gait)

  eg.

  • can’t walk on carpet but can walk on tile (so you stop -. your gait freezes)

Micrographia

Writing gets smaller or is small all the way through

(a form of bradykinesia)

Hypomimia

• A medical sign where there is a reduced degree or absence of facial expression which is caused by motor impairment (weakness or paralysis of the facial muscles). 

• socially restrictive

Persons receiving excessive ____ treatments and thereby losing facial expression features may be incorrectly identified as suffering from hypomimia.

Botox (based around paralysing facial features)

What is the first symptom to appear

Tremor

• hard to brush off a tremor (like you can the other symptoms)

Tremor

• Caused by loss of the inhibitory influence of dopamine in the basal ganglia.

• Usually 1 sided initially, the symmetric later

• Usually disappears upon voluntary movement

  • patients are asked to run, jog, be active to offset the tremor

    • like boxing (variety of movements and works upper and lower extremity)

• Tends to affect arm more than leg

  • (is this because arm has less voluntary movement

• Increased by stress or anxiety (increases acetylcholine)

• Disappears with sleep

Postural Instability

• Loss of normal postural reflexes

• Takes about 5 yrs

  
  

  Disorders of:

  • Postural fixation

  • Equilibrium

  • Righting

Postural Fixation

• Involuntarily flexes the head and neck

• Characteristic posture: stooped, flexed, forward leaning

How does this affect centre of gravity?

• It goes forward → stability compromised

• 
  

Equilibrium

• Unable to adjust to tilting or falling: falls like a post if starts to tilt (no protective reactions)

• See this in gait, to stop from falling forward.

Righting

Can’t change from inclining to a standing position: can’t right themselves

What risk do all these postural disorders suggest?

• falls

• injuries (specifically head and fractures)

Parkinson’s patients have higher likelihood of:

Falls: 70%

Injuries: 40%

Fractures: 25%

Falls: 70%

Injuries: 40%

Fractures: 25%

Muscle performance

• Weaker muscles in PD 

• Fatigue is a very common symptom

• Off/on with dopamine replacement medication

Motor Learning

• ‘Procedural learning’ deficits most common

  • Can learn facts by conscious awareness (declarative learning)

  • But can’t learn a motor skill by ‘practice’

  • Can’t learn to crochet but can learn the capital of france

Gait

• Up to 1/3^rd of patients with PD have postural instability and gait disturbances.

• Cane, walker

• Gait changes occur in later stages (5 years after diagnosis)

Sensation

• No primary sensory loss (tactile).

• May experience intermittent numbness ( ? dyskinesis, ? rigidity)

  • numbness however, is not a direct result of parkinson’s

Speech

• Impaired in 75-90% of patients

Voice

• ‘Hypokinetic dysarthria’ (decreased volume, monotone, distorted articulation, uncontrolled speech rate)

• cannot generate an emotive vocal pattern

• impacts ability to socially engage

Dysphagia (impaired swallowing)

• occurs in up to 95% of patients

• often an early symptom (but can be ignored - oh im just getting old…)

• Affects multiple phases of swallowing

  • abnormal tongue control

  • difficulty with chewing and bolus formation

  • delayed swallow response and peristalsis (inability for swallowing muscles to work)

• often get excessive drooling (sialorrhea)

Risk:

• Choking or aspiration pneumonia

Dementia

• In 20-40% of patients

• Dementia risk among PD patients over 80, is 4x greater than those under 80 years

• Usually within 10 years of PD onset

Olfactory dysfunction: Up to __% of patients with PD lose sense of smell

• Up to 100%!!! of patients with PD

  • We dont know why

Parkinson’s is: (summary)

Degeneration of dopaminergic nigrostriatal pathway causes dopamine depletion in the basal ganglia.

• results in imbalance between excitatory and inhibitory mechanisms.

PD lead to… (summary

• Primarily motor effects, but other impairments are possible. 

• Rigidity, NOT spasticity

• Progressive disease