Parkinson’s Disease

Nature, Nurture, & NeurodegenerationDecember 9th, 2008

8am

Parkinson’s disease: Learning Objectives

• Argue either for or against the existence of Parkinson’s disease as a distinct entity, utilizing clinical, pathological, and molecular genetic criteria

• Discuss the interaction of nature & nurture in the pathogenesis of Parkinson’s disease

• Define “tremor coactus”, and describe how to distinguish it from other forms of tremor

• Define “scelotyrbe festinans”, and do the same

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.”

Clinical definitions

Parkinsonism1. Resting tremor2. Bradykinesia3. Cogwheel rigidity4. Impaired postural

reflexes

Parkinson DiseaseParkinsonism, plus1. Asymmetric onset2. DOPA responsive3. Absence of

1. Saccadic problems2. Early, severe

orthostasis

4. Lewy bodies in SN

DISEASE DISTINGUISHING

FEATURES

RESPONSE TO

L-DOPA

Progressivesupranuclear palsy

Verticalophthalmoplegia,Postural instability

Good response rarelyevident

Multiple systematrophy

Early dysautonomia,Cerebellar

dysfunction

Initially in 20%,sustained in 10-15%

Corticobasaldegeneration

Cortical dysfunction,Alien-limb

Usually negligible

Other “Parkinsonian” Diseases

Pathologic definitions (20th Century)

• Lewy bodies within damaged substantia nigra (and other brainstem pigmented nuclei)

• “Incidental” Lewy bodies represent pre-clinical Parkinson’s disease

The genetic revolution: 12 linked loci, 6 genes cloned

Acronym Inheritance

Locus Protein

PARK1 AD 4q αsynuclein

PARK8 AD 12q LRRK2

PARK2 AR 6q Parkin

PARK6 AR 1p PINK1

PARK7 AR 1p DJ-1

PARK9 AR 1p ATP13A2

The synuclein age

• Autosomal dominant PD traced to a point mutation in α-synuclein gene

• α-synuclein is major protein component of Lewy bodies

• Function of α-synuclein still unclear, but it appears to modulate neurotransmitter vesicle function

Lewy bodies (and Lewy neurites) involve brainstem pigmented neurons in an ascending pattern: DMN of vagus, then locus ceruleus, then substantia nigra

Leucine-rich repeat kinase 2 (LRRK2)

• Most common cause of familial PD• >50 variants; often very low penetrance• G2019S in 2% of idiopathic PD, 20% of

PD in Ashkenazi Jews, 40% of PD in Arabs

• Clinically identical to sporadic PD, but marked heterogeneity within SN: LBs, no LBs, or NFTs (even in a single family)

• All G2019S carriers with hyposmia showed synuclein pathology in anterior olfactory nucleus

Parkin & PINK1-associated PD

• Parkin mutations are the most common known cause of early onset PD

• Mutations involving PINK1 (PTEN-induced putative kinase) are the most common known cause of Parkin-negative early onset PD

• Parkin appears be essential for maintaining mitochondrial integrity

• PINK1 regulates localization of Parkin to the mitochondria

Epidemiology of PD

Increased risk1. Pesticide

exposure2. Pre-

menopausal oopherectomy

3. Familial aggregation

Decreased risk1. Smoking2. Coffee3. High plasma

urate

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)

Mitochondrial dysfunction

(Parkin, PINK-1)

Environmental oxidative stress with

free radical generation

Proteosomal dysfunction

Cell Death

Parkinson’s Disease

Inclusion formation

Chapter I. Definition-History-Cases

• Insidious onset of a sense of weakness with proneness to trembling

• 12 months later, similar problems in other parts

• Proneness to falling due to altered proprioception

• Tremor interferes with reading, writing, and eating

Chapter I. Definition-History-Cases

• Propensity to lean forward, necessitating the adoption of an unwilling running pace

• Tremor interferes with sleep• “..bowels, which had been all along torpid,

now, in most cases demand stimulating medicines of very considerable power..”

• Unable to chew or swallow food• Constant drooling, incontience, delerium

PATHOGNOMONIC SYMPTOMS EXAMINED

• TREMOR COACTUS: Involuntary tremulous motion, with lessened voluntary muscular power, in parts, not in action, and even supported

• SCELOTYRBE FESTINANS: A propensity to bend the trunk forwards, and to pass from a walking to a running pace (literally “hastening lameness”)

Wilhelm von Humboldt (1767-1835)

• Educational reformer, statesman serving Frederick William III, King of Prussia and a philologist

• supplemented James Parkinson's description with micrographia, and dysdiadochokinesia.

SUPPOSED PROXIMATE CAUSE

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.

..but how few can estimate the benefits bestowed on mankind, by the labours of a Morgagni, Hunter, or Baillie.

FINIS.