Chapter 18:  Parkinson's Disease

• Definitions:
  • Tremor: rhythmic/oscillatory movement -- around a joint
    • Resting tremor (Parkinson's disease): , associated with:
      • rigidity
      • impairment of volitional movement
    • Essential Tremor:
      • postural tremor (clearly observable)
    • Intentional Tremor:
      • brain stem/cerebellar lesion (particularly with superior cerebellar peduncle involvement
      • May be associated with alcohol/other drug toxicities
  • Chorea: involuntary muscle jerks; unpredictable
    •  hereditary
    • secondary to drug treatment/various physiological disorders
    • volitional activity impairment
    • different parts of the body affected
      •  limb proximal muscles-- most severely affected
        •  violent movements -- ballismus
  • Athetosis:slow, writhing abnormal movement
  • Dystonia:postural abnormality -- associated with sustained, abnormal movement
    • Athetosis/dystonias -- causes/characteristics:
      • brain damage (perinatal)
      • focal/generalized cortical lesions
      • adverse effect associated with certain drugs (e.g. antipsychotics)
      • associated with various neurological disorders:
      • unknown causes:
        •  idiopathic torsion dystonia
        •  dystonia musculorum deformans
  • Tics: sudden, abnormal coordinated movements
    • Characteristics:tics
      • single/multiple; transient/chronic
        •   Chronic, multiple tics: Gilles de la Tourette's syndrome (Tourette's syndrome)
      • repetitive (especially around head/face, in children)
      • voluntary suppression: for limited amount of time
      • Common tics:
        • shoulder shrugging
        • repetitive sniffing

Parkinson's Disease

Overview

• Disease Characteristics:
  • Chronic, progressive
  • begins in middle/late life and leads to progressive disability
  • Affects all ethnic groups
  • Equal gender distribution
  • Frequency:
    • General Population: 1-2 per 1000 people
    • Population > 65 years: 1 per 100 persons
      •  Age group -- 65-74 years of age: 15%
      •  Age group -- > 85 years of age: > 50%
• Neuroanatomical Correlates of Disease
  • Normal anatomy and physiology:
    •  Cell bodies from the substantia nigra pars compacta provides dopaminergic input to the striatum (basal ganglia)
    •  dopaminergic neurons + cholinergic striatal interneurons modulate monosynaptic GABA inhibitory output  to the globus pallidus internus and pars reticulata of the substantia nigra
    •  globus pallidus internus transmits GABA-mediated inhibition to the ventrolateral/ventroanterior thalamic nuclei (direct pathway, striatal D₁-mediated)
    •  globus pallidus externus transmits  via subthalamic nuclei (indirect pathway, striatal D₂-mediated) excitatory (Glutamate) input to the globus pallidus internus.
  • Neuronal loss in Parkinson's Disease
    • loss of substantia nigra pars compacta cells cause reduced nigral-striatal dopamine input to the putamen. There are two effects:
      1. loss of an striatal excitatory dopamine input (D₁-mediated direct pathway)
         • loss of dopamine-mediated excitation of an inhibitory GABA pathway (DeLong's model) causes GPi hyperactivity which leads to excessive thalamic inhibition (GPi output is inhibitory (GABA)
      2. loss of an striatal inhibitory dopamine input (D₂-mediated, indirect pathway)
         • loss of dopamine-mediated inhibition of a GABA inhibitory pathway more GABA release and GPe hypoactivity
         • GPe hypoactivity decreases GABA (inhibitory) output to subthalamic nuclei.
         • Increased subthalamic nuclei excitatory output (glutamate-mediated) further increases GPi hyperactivity leading to further thalamic inhibition.

• Basal Ganglia Anatomy
  • GABA -- basal ganglia inhibitory neurotransmitter
  • Glutamate -- excitatory neurotransmitter (subthalamic nuclei ® thalamus)

• Summary: Net Effect
  • Loss of striatal dopamine increases GPi activity by both direct and indirect mechanisms leading to increased thalamic inhibition and reduced thalamic-mediated motor cortex excitation (bradykinesia): see Iacona et al., Am. Surg 60: 777-782, 1994);
  • Recall dopamine normally activates excitatory D1 receptors (direct pathway) and represses inhibitory D2 receptors (in direct pathway) -- with dopamine depletion:
    1.  decreased activity of direct pathway (less GPi inhibition) leads to  increased GPi activity which results in  increased thalamic inhibition
    2.  increased activity of the indirect pathway (more GPe inhibition) leads to less subthalamic nuclei inhibition and increased GPi activity resulting in increased thalamic inhibition
• Pathogenesis
  • Chemically-Induced: in primates by --
    •  1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which is
    •  converted to the active form by monoamine oxidase
    •  active toxin: MPP+ -- N-methyl-4-phenylpyridinium
      • MPP+:
        • taken up into nerve terminals by dopamine reuptake system (active transport)
        • inhibits oxidative phosphorylation (possibly complex I; respiratory chain site)
        • may also produce oxidative stress/free radicals
        • Consequence:
          1. nigro-striatal neuronal death
          2. basal ganglia dopamine depletion
          3. Parkinson's disease
  • Parkinson's disease: Cause
    • unknown
    •  Possibilities include:
      • environmental toxin
      • endogenous toxins (perhaps related to free radicals generation)
    • Genetic Aspect: uncertain
• Clinical Manifestations:
  •  Tremor: characteristics --
    • Frequency: usually 4-to 6-Hz
      • 7-8-Hz in about 10%-15% (resembling essential tremor)
    • resting tremor (worsens with stress)
    • initially:
      • rhythmic flexion-extension of: fingers, hand, foot
      • rhythmic pronation-supination to forearm
    • may be associated with one limb or to limbs ipsilateral, initially, then becoming more widespread
  •  Rigidity:increased resistance to passive movement
    • common feature (flexed posture)
  •  Bradykinesia:  most disabling disease manifestation
    • severest form -- akinesia
    • Characteristics:
      • voluntary movement: slowness
  •  Flat affect (flat facial expression)
    • widened palprebral fissures
    • infrequent blinking
  •  Other Effects:
    •  Blepharoclonus: (closed eyelid fluttering)
    •  Blepharospasm: (eyelid closure -- involuntary)
    •  Drooling
    •  Voice: hypophonic/poorly modulated
    •  Handwriting: small, tremulous, perhaps illegible
  •  Walking:
    • difficulty in initiation -- patients may increasingly leaned forward to begin movement
    • small, shuffling steps
    • no arm-swing
    • stopping difficulty
    •  festinating gait:
      • walking with increasing speed to keep from falling (because because of abnormal center of gravity)
  • Reflexes:
    • Tendon: unaltered
    • Tapping over the glabella: sustained blink response (Myerson's sign)
  •  Depression
  •  Impaired cognitive function
    • may reach dementia in advanced cases

1. Primary Reference: Aminoff, M. J. Pharmacologic Management of Parkinsonism & Other Movement Disorderslogy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 450-463
2. Primary Reference: Aminoff, M. J. Parkinson's Disease and Other Extrapyramidal Disorders, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 2356-2362
3. Iacona et al., Am. Surg 60: 777-782, 1994