Parkinsons Disease: Endlessly Fascinating Facts

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Parkinsons Disease Endlessly Fascinating Facts

• Resident Conference
• 6 May 2009
• J. Peacock MD, PhD

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Parallel organization of motor non-motor basal
ganglia loops
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Well-known Cardinal Features

• Resting Tremor (3 5 Hz)
• Rigidity (cogwheel, paratonia)
• Bradykinesia
• Loss of balance

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Well-knownAssociated Features - 1

• Hypomimia - masked face reptilian stare
• Hypophonia - low volume, rapid speaking
• Saccadic visual pursuit
• Difficulty in arising from a chair

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Well-knownAssociated Features - 2

• Shuffling gait, decreased stride
• Problems overcoming inertia
• Cant start cant stop
• Freezing
• Speeding up

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Well-knownAssociated Features - 3

• Wooden (en bloc) movements
• Postural changes, stiff, stooped
• Altered center of gravity
• Tendency to retropulsion
• Decreased arm swing
• Compass turn

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Well-knownAssociated Features - 4

• Decremental amplitude on finger tapping
  decreased dexterity
• Postural lightheadedness
• Loss of olfactory sense early
• Law-abiding wont jay walk
• Mate for life spousal fidelity

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Non-motor Problems in PD

• Autonomic Dysfunction
• Neuropsychiatric Symptoms
• Sensory Phenomena
• Cognitive Impairment
• Sleep Disturbances
• Sensory Phenomena

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Dysautonomia In PD

• Dysphagia including sialorrhea
• Constipation
• Urinary problems
• Orthostatic hypotension
• Sexual problems
• Impaired thermoregulation

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Overlap of problems with behavior, emotions
memory

• Cause symptoms in the areas listed in the next
  slide
• Note these are symptoms that can occur, but do
  not necessarily happen in any person with
  Parkinsons disease

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Overlap --

• Neuropsychiatric Symptoms
• Cognitive Impairment
• Sleep Disturbances
• Autonomic Dysfunction
• Sensory Phenomena

Dr. Eugene Lai PADREC Meeting 2003
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Non-motor FrequencyFrom Eugene Lai, MD
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Neuropsychiatric Symptoms

• Depression
• Hallucinations (formed visual images of silent
  persons or animals)
• Delirium
• Anxiety - Panic
• Agitation

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Cognitive Impairment - 1

• May affect up to 40
• Late feature of Parkinsons disease
• Ddx
• PD dementia vs. AD
• vs. Diffuse Lewy body dementia
• vs. Vascular Dementia

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Cognitive Impairment - 2

• Frontal executive problems visuo-spatial
  problems, temporal sequencing, decreased memory
  and attention
• Increased burden for caregivers

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Sleep Disturbances

• Insomnia
• REM behavior disorder
• Nightmares
• Obstructive sleep apnea
• Excessive daytime sleepiness

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Sensory Phenomena In Parkinsons

• Cramps
• Dystonic Pain
• Pain of immobility
• Heaviness in limbs
• Restless leg Symptoms

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Lewy Bodies

• Neuropathologic signature of PD
• Found also in
• Lewy Body dementia
• Multiple system atrophy
• Hallervorden-Spatz disease
• Widely distributed in brain body

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Lewy Body Distribution - 1

• Substantia nigra
• Hypothalamus
• Sympathetic nervous system
• Intermediolateral nucleus of spinal cord plus
  sympathetic ganglia ? hypotension

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Lewy Body Distribution - 2

• Parasympathetic system
• Dorsal vagal nucleus ? dysphagia
• Sacral parasympathetic nucleus --gtDysuria
• Myenteric plexus --gt Constipation

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Lewy Body Distribution - 3

• Cardiac plexus --gt Cardiac arrhythmias
• Pelvic plexus --gt Pelvic floor dysfunction
• Adrenal medulla --gt Blood pressure changes

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Lewy Bodies Are Composed Of Alpha Synuclein

• A presynaptic protein
• Identified by antibody staining
• Found in Lewy Bodies
• But also Neurons, dentrites, oligodendroglia
  in PD, etc.

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Alpha Synuclein - 2

• The gene for a-synuclein (SNCA) is on chromosome
  4q21
• One form of hereditary PD is due to mutations in
  SNCA
• Another form is due to a triplication of SNCA
• Alpha-synuclein is also referred to as the
  non-amyloid component of senile plaques precursor
  protein (NACP)

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Synucleinopathies

• Parkinsons disease
• Lewy body dementia
• Multiple system atrophy
• Shy Drager variant
• Hallervorden-Spatz disease
• Striatonigral degeneration with iron deposition

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Emerging Concept

• Alpha synuclein is to Parkinsons disease as
• Beta amyloid is to Alzheimers disease, i.e.
• A-synucleinPDB-amyloidAD
• NOTE Both can be expressed in the same
  individual

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More Fascinating Facts Parkinsons Disease-1

• Genetic influences 8X increase in relatives of
  early onset 3X increase in those of late onset
  PD
• Children of younger PD parents at greater risk
  for PD than if they had older parents

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More Fascinating Facts Parkinsons Disease-2

• APO E3/E4 OR E4/E4 ASSOC WITH EARLY ONSET PD
• CAFFEINE NICOTINE PROTECTIVE AGAINST PD
• EXERCISE IS ALSO PROTECTIVE

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Basis for non-motor symptoms

• The next slide shows the physiological
  organization of the non-motor system in the basal
  ganglia that is disrupted by Parkinsons disease

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Overlap of problems with behavior, emotions
memory

• Cause symptoms in the areas listed in the next
  slide
• Note these are symptoms that can occur, but do
  not necessarily happen in any person with
  Parkinsons disease

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Overlap of problems with behavior, emotions
memory

• Neuropsychiatric Symptoms
• Cognitive Impairment
• Sleep Disturbances
• Autonomic Dysfunction
• Sensory Phenomena

Dr. Eugene Lai PADREC Meeting 2003
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Non-motor Frequency
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Neuropsychiatric Symptoms

• Depression
• Hallucinations
• Delirium
• Anxiety
• Panic
• Agitation

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Neuropsychiatric Treatment

• Reduce or stop medications
• Identify treat medical problems
• Antidepressants
• Atypical Neuroleptics
• Anxiolytics
• Keep active exercise
• Educate Caregivers
• Psychological Counseling

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Cognitive Impairment

• May affect up to 40
• Late feature of PD
• Dx PD vs AD vs Lewy Body disease (LBD) vs
  vascular disease
• Frontal Executive Problems Visuospatial
  problems, temporal sequencing, memory,
  attention
• Burden for caregivers

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Comparative cognitive changes in PD, LBD, AD - 1

• Appear 5-10 years after motor symptoms (sx) in PD
  may never develop in some individuals
• Appear at onset, often with visual hallucinations
  in LBD before motor sx in 1-2 years. Motor
  symptoms respond incompletely to L-Dopa

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Comparative cognitive changes in PD, LBD, AD - 2

• May fluctuate early in course in LBD
• Appear at onset in AD. Motor sx like PD develop
  late, if at all, respond poorly to L-Dopa

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Treatment Of Cognitive Impairment

• No good medical therapy
• ? Cholinesterase inhibitor (Aricept, Razadyne, or
  Exelon)
• Check for medications affecting cognition
  memory
• Symptomatic behavioral therapy
• Caregiver education

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Sleep Disturbances (dysomnia)

• Insomnia
• REM behavior disorder
• Nightmares
• Obstructive sleep apnea
• Excessive daytime sleepiness

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Rx Dysomia--1

• Treat depression anxiety
• Add Sinemet CR at bedtime
• Sleep hygiene program
• Short acting sedative hypnotics
• Minimize nocturia (urination at night)

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Rx Dysomia--2

• Clonazepam for rapid eye movement (REM) sleep
  problems
• Stop tricylics and monoamine oxidase inhibitors
• Avoid evening stimulants
• Evaluate sleep disorder

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Dysautomia (dysfunction of the autonomic system)
in PD

• Constipation
• Urinary problems
• Orthostatic hypotension
• Sexual problems
• Impaired thermoregulation
• Dysphagia (impaired swallowing)
• Sialorrhea (drooling)

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Rx Of Constipation

• Dietary modification
• Increase physical activity
• Stop anticholinergics (e.g. Artane)
• Stool softener
• Bulk fibers
• Lactulose
• Mild laxative
• Education

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Rx Of Dysuria

• Nocturia, frequency, urgency
• Reduce evening fluids
• Elevate head of bed
• Medication (oxybutynin, tolterodine)
• Possible urologic evaluation

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Rx Of Orthostatic Hypotension In PD

• Eliminate anti-hypertensives
• Behavioral modification
• Increase salt and fluids
• Support hose
• Elevate head of bed
• RX Fludrocortisone or midodrine

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Sensory Phenomena In PD

• Cramps
• Dystonic pain
• Pain of immobility
• Heaviness in limbs
• Restless leg syndrome

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Rx Of Sensory Problems

• Stretching exercises
• Medication adjustment
• Physical therapy
• Baclofen or tizanidine
• NSAIDs Non-steroidal anti-inflamatory
  medication
• Botulinum toxin

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Summary

• Behavior, emotions, memory are affected in
  different ways in different individuals with
  Parkinsons disease.
• These changes have a profound effect on their
  lives their families.
• Management of these, often complex, non-motor
  issues are as important as treatment of motor
  symptoms

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Changes in behavior in PD

• Do changes in the mirror neuron system in PD
  affect behavior?

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What is a mirror neuron?

• It is a neuron that reacts when Person A makes a
  movement, but also when person A watches Person B
  executing the same movement.
• Monkey see Monkey do!

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The discovery of mirror neurons, quite by chance

• Scientists recorded activity in a single neuron
  in a monkeys frontal cortex while the monkey
  moved its hand.
• During a break, one of the men ate a banana while
  the monkey was watching. That same neuron fired!
• Fogassi, Rizzolatti, Gallese in Parma, Italy

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Area F5 in the Macaque monkey brain
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Evidence from human MRI

• Neurons that respond to watching someone eating a
  chip, also respond to just hearing the snap of
  the chip
• Neurons that respond to watching an action, also
  respond to reading about that action
• Autistic children have no mirror neurons

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Functional MRI in Man
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Why are mirror neurons important?

• First, for language
• These neurons are located near the motor speech
  (Brocas) area
• Language probably evolved as humans involuntarily
  mirrored each others hand movements
• Facilitate multi-tasking

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Why are mirror neurons important? - continued

• Second for empathy intuition
• Empathy is critically important for socialization
  

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Evidence for empathy

• Functional MRI study of 14 male subjects
• First condition - Smell disgusting odorants
• Second condition view video of others showing
  facial expressions of disgust to those bad smells

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Bringing this back to Parkinsons disease

• Next slide

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• Subjects viewed facial expressions of disgust
• Response of normal controls
• Response of PD subjects off L-Dopa
• Response of same subjects on L-Dopa