Parkinson’s Disease Nature, Nurture, & Neurodegeneration December 9 th , 2008 8am
Parkinson’s disease: Learning Objectives <ul><li>Argue either for or against the existence of Parkinson’s disease as a dis...
Arch Neurol. 2008 Jun;65(6):705-8 .  “ The final straw that will break the nosologic back of Parkinson disease is the accu...
Clinical definitions <ul><li>Parkinsonism </li></ul><ul><li>Resting tremor </li></ul><ul><li>Bradykinesia </li></ul><ul><l...
Other “Parkinsonian” Diseases
Pathologic definitions (20 th  Century) <ul><li>Lewy bodies within damaged substantia nigra (and other brainstem pigmented...
 
 
The genetic revolution:  12 linked loci, 6 genes cloned ATP13A2 1p AR PARK9 DJ-1 1p AR PARK7 PINK1 1p AR PARK6 Parkin 6q A...
The synuclein age <ul><li>Autosomal dominant PD traced to a point mutation in  α -synuclein gene </li></ul><ul><li>α -synu...
<ul><li>Lewy bodies (and Lewy neurites) involve brainstem pigmented neurons in an  ascending  pattern: DMN of vagus,  then...
Leucine-rich repeat kinase 2 (LRRK2) <ul><li>Most common cause of familial PD </li></ul><ul><li>>50 variants;  often very ...
Parkin & PINK1-associated PD <ul><li>Parkin mutations are the most common known cause of early onset PD </li></ul><ul><li>...
 
Epidemiology of PD <ul><li>Increased risk </li></ul><ul><li>Pesticide exposure </li></ul><ul><li>Pre-menopausal oopherecto...
 
When only the DMN-V contains Lewy bodies, synuclein pathology is also found in the anterior olfactory system and the enter...
Mitochondrial dysfunction (Parkin, PINK-1) Environmental   oxidative stress with free radical generation Proteosomal dysfu...
 
Chapter I. Definition-History-Cases <ul><li>Insidious onset of a sense of weakness with proneness to trembling </li></ul><...
Chapter I. Definition-History-Cases <ul><li>Propensity to lean forward, necessitating the adoption of an unwilling running...
PATHOGNOMONIC SYMPTOMS EXAMINED <ul><li>TREMOR COACTUS:  Involuntary tremulous motion, with lessened voluntary muscular po...
Wilhelm von Humboldt (1767-1835) <ul><li>Educational reformer, statesman serving Frederick William III, King of Prussia an...
SUPPOSED PROXIMATE CAUSE <ul><li>A diseased state of the medulla spinalis, in that part which is contained in the canal, f...
 
..but how few can estimate the benefits bestowed on mankind, by the labours of a Morgagni, Hunter, or Baillie. FINIS.
 
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Parkinson\'s Disease

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Parkinson\'s Disease

  1. 1. Parkinson’s Disease Nature, Nurture, & Neurodegeneration December 9 th , 2008 8am
  2. 2. Parkinson’s disease: Learning Objectives <ul><li>Argue either for or against the existence of Parkinson’s disease as a distinct entity, utilizing clinical, pathological, and molecular genetic criteria </li></ul><ul><li>Discuss the interaction of nature & nurture in the pathogenesis of Parkinson’s disease </li></ul><ul><li>Define “tremor coactus”, and describe how to distinguish it from other forms of tremor </li></ul><ul><li>Define “scelotyrbe festinans”, and do the same </li></ul>
  3. 3. Arch Neurol. 2008 Jun;65(6):705-8 . “ The final straw that will break the nosologic back of Parkinson disease is the accumulating genetic evidence.”
  4. 4. Clinical definitions <ul><li>Parkinsonism </li></ul><ul><li>Resting tremor </li></ul><ul><li>Bradykinesia </li></ul><ul><li>Cogwheel rigidity </li></ul><ul><li>Impaired postural reflexes </li></ul><ul><li>Parkinson Disease </li></ul><ul><li>Parkinsonism, plus </li></ul><ul><li>Asymmetric onset </li></ul><ul><li>DOPA responsive </li></ul><ul><li>Absence of </li></ul><ul><ul><li>Saccadic problems </li></ul></ul><ul><ul><li>Early, severe orthostasis </li></ul></ul><ul><li>Lewy bodies in SN </li></ul>
  5. 5. Other “Parkinsonian” Diseases
  6. 6. Pathologic definitions (20 th Century) <ul><li>Lewy bodies within damaged substantia nigra (and other brainstem pigmented nuclei) </li></ul><ul><li>“ Incidental” Lewy bodies represent pre-clinical Parkinson’s disease </li></ul>
  7. 9. The genetic revolution: 12 linked loci, 6 genes cloned ATP13A2 1p AR PARK9 DJ-1 1p AR PARK7 PINK1 1p AR PARK6 Parkin 6q AR PARK2 LRRK2 12q AD PARK8 α synuclein 4q AD PARK1 Protein Locus Inheritance Acronym
  8. 10. The synuclein age <ul><li>Autosomal dominant PD traced to a point mutation in α -synuclein gene </li></ul><ul><li>α -synuclein is major protein component of Lewy bodies </li></ul><ul><li>Function of α -synuclein still unclear, but it appears to modulate neurotransmitter vesicle function </li></ul>
  9. 11. <ul><li>Lewy bodies (and Lewy neurites) involve brainstem pigmented neurons in an ascending pattern: DMN of vagus, then locus ceruleus, then substantia nigra </li></ul>
  10. 12. Leucine-rich repeat kinase 2 (LRRK2) <ul><li>Most common cause of familial PD </li></ul><ul><li>>50 variants; often very low penetrance </li></ul><ul><li>G2019S in 2% of idiopathic PD, 20% of PD in Ashkenazi Jews, 40% of PD in Arabs </li></ul><ul><li>Clinically identical to sporadic PD, but marked heterogeneity within SN : LBs, no LBs, or NFTs (even in a single family) </li></ul><ul><li>All G2019S carriers with hyposmia showed synuclein pathology in anterior olfactory nucleus </li></ul>
  11. 13. Parkin & PINK1-associated PD <ul><li>Parkin mutations are the most common known cause of early onset PD </li></ul><ul><li>Mutations involving PINK1 (PTEN-induced putative kinase) are the most common known cause of Parkin-negative early onset PD </li></ul><ul><li>Parkin appears be essential for maintaining mitochondrial integrity </li></ul><ul><li>PINK1 regulates localization of Parkin to the mitochondria </li></ul>
  12. 15. Epidemiology of PD <ul><li>Increased risk </li></ul><ul><li>Pesticide exposure </li></ul><ul><li>Pre-menopausal oopherectomy </li></ul><ul><li>Familial aggregation </li></ul><ul><li>Decreased risk </li></ul><ul><li>Smoking </li></ul><ul><li>Coffee </li></ul><ul><li>High plasma urate </li></ul>
  13. 17. When only the DMN-V contains Lewy bodies, synuclein pathology is also found in the anterior olfactory system and the enteric nervous system (including the medulla spinalis )
  14. 18. Mitochondrial dysfunction (Parkin, PINK-1) Environmental oxidative stress with free radical generation Proteosomal dysfunction Cell Death Parkinson’s Disease Inclusion formation
  15. 20. Chapter I. Definition-History-Cases <ul><li>Insidious onset of a sense of weakness with proneness to trembling </li></ul><ul><li>12 months later, similar problems in other parts </li></ul><ul><li>Proneness to falling due to altered proprioception </li></ul><ul><li>Tremor interferes with reading, writing, and eating </li></ul>
  16. 21. Chapter I. Definition-History-Cases <ul><li>Propensity to lean forward, necessitating the adoption of an unwilling running pace </li></ul><ul><li>Tremor interferes with sleep </li></ul><ul><li>“ ..bowels, which had been all along torpid, now, in most cases demand stimulating medicines of very considerable power..” </li></ul><ul><li>Unable to chew or swallow food </li></ul><ul><li>Constant drooling, incontience, delerium </li></ul>
  17. 22. PATHOGNOMONIC SYMPTOMS EXAMINED <ul><li>TREMOR COACTUS: Involuntary tremulous motion, with lessened voluntary muscular power, in parts, not in action, and even supported </li></ul><ul><li>SCELOTYRBE FESTINANS: A propensity to bend the trunk forwards, and to pass from a walking to a running pace (literally “hastening lameness”) </li></ul>
  18. 23. Wilhelm von Humboldt (1767-1835) <ul><li>Educational reformer, statesman serving Frederick William III, King of Prussia and a philologist </li></ul><ul><li>supplemented James Parkinson's description with micrographia, and dysdiadochokinesia. </li></ul>
  19. 24. SUPPOSED PROXIMATE CAUSE <ul><li>A diseased state of the medulla spinalis, in that part which is contained in the canal, formed by the superior cervical vertebræ, and extending, as the disease proceeds, to the medulla oblongata. </li></ul>
  20. 26. ..but how few can estimate the benefits bestowed on mankind, by the labours of a Morgagni, Hunter, or Baillie. FINIS.
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