� Early Parkinson’s disease

� Pathophysiology

� Is Parkinson’s a syndrome?

� Therapeutic approaches

� Stages

� The future

� 1000 BC descriptions in Indian and Chinese texts of probable Parkinson’s

� 1680 – rest tremor described (da la Böe)

� 1817 – An essay on the shaking palsy

� 1870s – refinement by Charcot and others

Outlines of Orcytology Parkinsonia dorsetentsis

� “a sympathetic concern, and a tender

interest for the sufferings of others, ought

to characterize all those who engage

themselves in a profession, the object of

which should be to mitigate, or remove,

one great portion of the calamities to

which humanity is subject”

Long before rigidity actually develops,patients have significant difficulty performingordinary activities: this problem relates toanother cause. In some of the various patientsI showed you, you can easily recognize howdifficult it is for them to do things even thoughrigidity or tremor is not the limiting feature.Instead, even a cursory exam demonstratesthat their problem relates more to slowness inexecution of movement rather than to realweakness.

In spite of tremor, a patient is still able to do

most things, but he performs them with

remarkable slowness. Between the thought

and the action there is a considerable time

lapse. One would think neural activity can

only be effected after remarkable effort.

� Rejected the name “paralysis agitans” or

“shaking palsy”

� Differentiated from multiple sclerosis

� Noted two types – tremorous dominant

and the akinetic-rigid form

� There is an aspect of marked mental

hebetude, or at all events an extreme

slowness of expression, so that it is difficult

to elicit answers to questions about his

history… Yet we contrive to get, in

process of time, though the task is

laborious, a fair amount of information

from him. The face wears a peculiarly

stolid expression.

� The movement of the fingers at the

metacarpalphalangeal joints is similar to

that by which Orientals beat their small

drums.

Loss of dopaminergic neurons of the

pars compacta in the substantia

nigra

and other areas

www.urmc.rochester.edu

Lewy bodies

Lewy body

abnormal

accumulation of the

protein alpha-

synuclein bound to

ubiquitin in the

damaged cells.

This insoluble protein accumulates inside

neurones forming inclusions called Lewy

bodies

Frederic Levy 1885-1950

� Neuroleptic agents led to dramatic

improvements of schizophrenic and

other psychotic behaviours

But………

� induced parkinsonism largely

indistinguishable from Parkinson’s disease

itself

Progression of Parkinson Disease Jankovic Arch Neurol. 2005;62:351-352.

Progression

of

Parkinson’s

Disease

Nonlinear Progression of Parkinson Disease as Determined by Serial Positron

Emission Tomographic Imaging of Striatal Fluorodopa F 18 Activity Hilker et al

Arch Neurol. 2005;62(3):378-382.

PD may

become

symptomatic

when

striatonigral

neurons are

30% deplete

mean

preclinical

period of

5.6±3.2 years

Timing of Treatment Initiation in Parkinson’s

Disease: A Need for Reappraisal?

Schapira, Obeso Ann Neurol. 2006 Mar;59(3):559-62

Schapiro-

Obeso

hypothesis

The

compensatory

mechanisms

cause damage,

possibly

through release

of glutamate

which is

neurotoxic

Burn 2017

A 62 yr-old man with occupational pesticide exposure, drinks coffee & never a

regular smoker idiopathic RBD & olfactory loss

no constipation, depression or anxiety & no daytime somnolence

quantitative motor testing in the borderline/low-normal range (no expert

examination available)

•Step 1: Establish prior probability from available table as 1.25%

•Step 2: Calculate total LR = 1.2 (male) x 1.5 (pesticide) x 0.88 (coffee) x 1.25

(non-smoker) x 130 (RBD) x 4.0 (olfaction) x 0.8 (no constipation) x 0.85 (no

depression or anxiety), 0.88 (no somnolence) x 1.0 (borderline motor testing –

result omitted) = 616

•Step 3: Calculate post-test probability, using one of two methods:Make an exact

quantitative probability calculation using calculators. Result = 89%, or

From published table, LR must be 300. Actual LR >300, so patient meets criteria

for probable prodromal PD

Risk Quantification - Example

“One of the major developments in our attitude towards Parkinson’s disease has been the growth of a concept of Parkinsonism as a syndrome - a symptom –complex which may emanate from various causations. The ‘shaking palsy’ of James Parkinson is now looked upon as merely one representative (though still the most important) of a number of clinical events.”

parkinsonismparkinsonism

Idiopathic Parkinson’sIdiopathic Parkinson’s

Multiple system

atrophy

Multiple system

atrophyprogressive

supranuclearpalsy

progressive supranuclear

palsy

dementia with Lewy

bodies

dementia with Lewy

bodiesDrug induced parkinsonismDrug induced parkinsonism

vascular parkinsonism

vascular parkinsonism

“I have seen such patients

everywhere on the streets of

Rome, of Amsterdam, in Spain.

It is always the same picture.

They can be identified from

afar. You do not need a medical

history”

Parkinson advocated:

venesection, specifically advocating

blood letting from the neck, followed by

vesicatories to induce blistering and

inflammation of the skin. Small pieces of

cork to be purposefully inserted into the

blisters to cause a “sufficient quantity” of

purulent discharge

� Ordenstein

(Charcot’s

intern) –

belladonna

alkaloids

� quinquina, a quinine derivative, must be

diluted with syrup made from orange

rind and each dose of silver nitrate must

be impregnated in 9 g of soft bread to

form an ingestible pill.

1910 – Dopamine first

synthesised

1938 – discovery of

dopa decarboxylase

1950s – dopamine

localisation within the

brain (specifically in the

striatum)

1961 – first infusion of

levodopa

� Bed-ridden patients who were unable to sit up, patients who could not stand up when seated, and patients who when standing could not start walking performed all these activities with ease after L-dopa [levodopa]. They walked around with normal associated movements and they could even run and jump. The voiceless, aphonic speech, blurred by pallilalia and unclear articulation, became forceful and clear as in a normal person (Birkmayer and Hornykiewicz 1961).

APOMORPHINE LEVODOPA / CARBIDOPA

INTESTINAL GEL

DEEP BRAIN

STIMULATION

� Roots back to 1960s

� Vascular lesions in some patients

improved parkinsonian symptoms

� Rapid impulses to basal ganglia,

including STN, can markedly reduce

tremors

Worth 2015

Amudha 2015

1.6

years

Other Parkinsonian condition

Progressive Supranuclear Palsy

Dementia with Lewy Bodies

Multiple System Atrophy

Arteriosclerotic

pseudoparkinsonism (Vascular)

Drug Induced parkinsonism

Red flags

Culprit medication

History of strokes

Early falls

Symmetrical

Rapid onset / rapid progression

Poor response to levodopa

Early dementia or hallucinations

Cerebellar signs

Vertical gaze palsy

5.9

years

4.9

years

2.2

years

2.2

years

Stepwise drug reduction – psychosis and hallucinosis (Playfer & Hindle 2nd ed.)

� Adenosine 2a (A2a agonists)

� IPX066 – extended release levodopa

� XP21279 - sustained release L-dopa

� ND0611 - carbidopa subcutaneous

patch

� ?exenatide

� ?Foetal cell transplants