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Parkinson's Disease

lifang zhang
nxzhanglifang@163.com
2017.03.30
 Table of contents
• Introduction
• Epidemiology
• Anatomy
• Pathology
• Pathophysiology
• Etiology and risk factor
• Clinical Manifestations
• Dignosis
• Treament
 Introduction

Monograph by James Parkinson

(1817)
• “ motion, with
, in parts not in action and
even when supported; with a propensity to
and
the senses and
intellects being uninjured.”
 Introduction
• Idiopathic Parkinson disease (PD) is a chronic
degenerative disorder with characteristic
clinical findings, response to L-dopa
replacement therapy, and pathologic changes
in the brain.
• Parkinsonism is a term used to describe a
heterogeneous group of conditions that share
some of the clinical features of idiopathic PD
but differ partially in their clinical expression,
response to L-dopa therapy, and underlying
pathologic substrates.
 Epidemiology
• Primarily a disease of the elderly
• Affecting approximately 1.5% to 2.0% of
people aged 60 years and older.
• 4.5-21 cases per 100,000 population per year
• M/F = 3:2
• Prevalence increases with age
• Most instances are sporadic
The epidemic situation of Parkinson's disease

• The population prevalence of Parkinson‘s disease：

• 100~300/100000 population per year on
earth
• The older 65 years population prevalence of
Parkinson‘s disease：
• 1,700/100000 population per year
• The motality of PD 29.17%
 The epidemic situation of Parkinson's disease
The population prevalence of Parkinson‘s disease： 0.3%
North America Europe Asian

• 11~13/100 000 population per • 9~22/100 000 population • 1.5~17.0/100 000

year per year population year
• China 16.7/ 100 000
population per year
North America
Europe Asian

South American
• In older 70-79 years people
，2180/100 000 population
per year
Africa Oceanica
South American • In older 70-79
Oceanica years people
Africa • 1602/100000
a
Is bounded to the Sahara desert population per year
North state 436~557/100000
population per year
South state 7~20/100000
population per year

de Lau LM, Breteler MM. Lancet Neurol, 2006, 5:525-535.

Wirdefeldt K, et al. Eur J Epidemiol, 2011, 26 (Suppl 1):1-58.
Khedr EM, et al. Neuroepidemiology, 2012, 38:154-163.
Blanckenberg J, et al. J Neurol Sci, 2013, 335:22-25.
• The prevalence rates of the spectrum of neurological
disorders ：2394 per 100,000 population, providing a
rough estimate of over 30 million people with neurological
disorders (excluding neuroinfections and traumatic injuries).
• Prevalence and incidence rates of common disorders
including epilepsy, stroke, Parkinson's disease and tremors
 Anatomy

Internal
capsule

Putamen
Caudate
Nucleus
Globus
pallidus
 Anatomy
• Cells in substantia nigra produce/release
dopamine
• Dopamine released by SN neurons lands on
neurons of other brain centers, controlling
their firing
• Main targets are caudate nucleus and
putamen (corpus striatum )
• This basal ganglia pathway is involved in
regulation of movement
 Pathology

 Eosinophilic hyaline
inclusion bodies
 Spherical dense hyaline
core with a clear halo

Lewy Bodies
 Pathology
Normal

Lewy Bodies

PD

• substantia nigra cells including pigment is

decreased in PD
Pathology
The degree of Pathology for PD
5 neocortex Cognitive
, signs
6
4 The temporal nesocortex.
Thalamus Parkinsonism

3 Substantia nigra,Amygdala

Clinical
2 The locus coeruleus.
biomarkers
1 Dorsal motor nucleus of the
vagus nerve. Olfactory
structures
0 Stomach nerve plexue

Braak H, et al. Neurobiol Aging 2003; 24:197–211.

The progress of PD

100%
80%
the level of
dopamine

60%
40%
20 %
diagnosis
0%
4 — > 13 年
Braak H, et al. Neurobiol Aging 2003;24:197–211.
 Pathophysiology
Chemical Balance in Corpus Striatum

+ Excitatory
Cholinergic
pathway

BALANCE
- Inhibitory
Dopaminergic
pathway
Pathophysiology

Dopamine
Acetyl choline ( ACH )
 Etiology and risk factor
• Etiology
• Aging
• Environmental toxin
• Genetic factor
The number of PD per 100,000
Aging and PD
 Etiology and risk factor
• Etiology
• Aging
• Environmental toxin
• Genetic factor
 MPTP and PD
• The discovery in the 1980s of the neurotoxin
MPTP (1-methyl -4-phenyl -1,2,3,6-
tetrahydropyridine), a precursor of MPPP and
a byproduct of illicit(opioid) drug synthesis,
has contributed prominently to proposed
etiologies for PD.
• “The clinical features of the experimental Parkinson
model, obtained by means of MPTP inoculation in
various animals and their similarities to the analogous
human disease are described. We can conclude that the
MPTP discovery enhances the hypothesis that
Parkinson's disease can be also attributed to toxic
factors.”
 Mechanism of MPTP damaging the
DA neurons
MPTP
( Direct neurotoxin )
Microglia
Reactive
Dopaminergic microgliosis
neuronal damage

Self-propelling

Pro-inflammatory factors

( ROS, NO., TNF-, IL-1β, PGs )

 Etiology and risk factor
• Etiology
• Aging
• Environmental toxin
• Genetic factor
 Genetic factors
• Family history appears to be a strong predictor
• A total of 18 loci in various genes have now
been proposed for Parkinson disease.
Mutations within 6 of these loci (SNCA, LRRK2,
PRKN, DJ1, PINK1, and ATP 13A2) are well-
validated causes of familial parkinsonism.
 Risk factor

• GBA：glucocerebrosidase.RBD：R(apid)E(ye)M(ovement) sleep behaviour disorder

video
• SN+ is hyperechogenicity in the region of the substantia nigra using transcranial sonography
 Clinical Manifestations
Moter symptoms
Non-moter symptoms
 Motor symtom
– tremor
– bradykinesia
– rigidity
– postural instability
 Motor symtom
tremor：often appear as the first sign.
Characters: 4~6Hz, conspicuous at rest,
increase at times of emotional stress,
improves during voluntary activity, stop during
sleep, begin from hand , “N”
progression.Tremors can also eventually occur
in the head, lips, tongue, and feet.
 Motor symtom
– tremor
– bradykinesia
– rigidity
– postural instability
 Motor symtom
• Bradykinesia: slowness
and reduction of
voluntary movement,
difficult to initiate,
masked face,
hypophonia,
micrographia.
 Micrographia

“Today is a sunny day in Toronto"

Loop drawing: Amplitude Interloop distance
Mask face and Micrographia
 Motor symtom
– tremor
– bradykinesia
– rigidity
– postural instability
 Motor symtom

• Rigidity: lead pipe / cogwheel phenomenon.

Rigidity can be felt rather than seen, by slowly
passively rotating the patient’s wrist or elbow and
feeling resistance. The right and left sides often
differ.
 Motor symtom
– tremor
– bradykinesia
– rigidity
– postural instability
Motor symtom
• Abnormal gait and posture:
flexed posture; difficult to
get up, start walking, turn
or stop. Shuffling gait and
absence of the arm swing;
 Clinical Manifestations
Moter symptoms
Non-moter symptoms
 Nonmotor symtom
– Diminished sense of smell
– Sleep disturbance
– Depression
– Constipation
Todorova A, Jenner P, Ray Chaudhuri K. Pract Neurol, 2014, 14(5): 310-322.
 The relationship between non-
motor symptoms and HY grade
• A clinical research from 1307 PD cases
percentage percentage
HYstaging NMSS
（%） （%）
1 19.8 A. 无 0.8
2 42.3 B. 轻度 26.6
3 27.9 C. 中度 27.6
4 8.4 D. 重度 24.1
73.7%
5 1.5 E. 非常严重 20.9
 The nonmotor symptoms can
affect the patients quality of life

Quality of
life
motor motor+nonmotor

>
Depress
Apathy
 Diagnosis
There are currently no blood or laboratory tests that
have been proven to help in diagnosing
PD. Therefore the diagnosis is based on medical
history and a neurological examination. The disease
can be difficult to diagnose accurately.
Doctors may sometimes request imaging studies (i.e.
MRI’s or brain scans) or laboratory tests in order to
rule out other diseases.
MDS：movement disorder society，2015
Description of the Hoehn and Yahr staging
scale and disease phases
Subtypes of Parkinson’s disease
 Differential diagnosis of Parkinson’s diseases
Parkinsonian Syndrome Distinguishing Clinical Features
Progressive supranuclear Supranuclear ophthalmoplegia, with limitation of vertical
palsy morethan horizontal gaze;axial rigidity and neck extension; early
falls as a consequence of Impaired postural reflexes,neck
extension, and inability to look down.
Corticobasal ganglionic Apraxia,cortical sensory impairment,and alien-limb
degeneration phenomenon;severe unilateral rigidity;stimulus-sensitive
myoclonus
Diffuse Lewy body disease Early dementia;prominent visual hallucinations;extreme
sensitivity to extrapyramidal side effects of antidopaminergic
neuroleptic drugs
Vascular Parkinsonism "Lower-half" parkinsonism with rigidity in the legs and marked
gait impairment; other evidence of diffuse vascular disease
(corticospinal tract dysfunction, pseudobulbar palsy)
Multiple system atrophy Early and prominent features of autonomic dysfunction;evidence
of corticospinal tract dysfunction;cerebellar signs; stimulus-
sensitive myoclonus; vocal cord paresis
 Treament
• Replacement of the deficient dopamine：L-
dopa
• Dopaminergic agonists
• The selective monoamine oxidase B (MAO-B)
inhibitor selegiline
• The catechol-O-methyl (COMT) transferase
inhibitors
• Amantadine
• Anticholinergics Artane
levodopa and benserazide
• L-dopa
• benserazide a peripheral decarboxylase
inhibitor which prevents the peripheral
conversion of L-dopa to dopamine and thus
assuring delivery of adequate drug to the
central nervous system (CNS) while reducing
the incidence of peripheral dopaminergic
side effects such as nausea, vomiting, and
hypertension.
• 1/4 tid or qid one hour before meal
• Taking lower, more frequent doses of
levodopa (however, risk of wearing off
becomes a problem)
 Treament
• Replacement of the deficient dopamine：L-
dopa
• Dopaminergic agonists
• The selective monoamine oxidase B (MAO-B)
inhibitor selegiline
• The catechol-O-methyl (COMT) transferase
inhibitors
• Amantadine
• Anticholinergics Artane
 Dopaminergic agonists have been proposed as
alternative initial agents for symptomatic
treatment, but the evidence that early therapy
with dopaminergic agonists reduces the
subsequent risk of dopa-induced dyskinesias is
controversial.
Adding a dopamine agonist while lowering the
levodopa dose

pramipexole

Piribedil
 Treament
• Replacement of the deficient dopamine：L-
dopa
• Dopaminergic agonists
• The selective monoamine oxidase B (MAO-B)
inhibitor selegiline
• The catechol-O-methyl (COMT) transferase
inhibitors
• Amantadine
• Anticholinergics Artane
 selegiline

The selective monoamine

oxidase B (MAO-B)
inhibitor selegiline may
also provide early
symptomatic benefits.
Adding a MAO-B while
lowering the levodopa
dose
5mg-10mg qd po
 Treament
• Replacement of the deficient dopamine：L-
dopa
• Dopaminergic agonists
• The selective monoamine oxidase B (MAO-B)
inhibitor selegiline
• The catechol-O-methyl (COMT) transferase
inhibitors
• Amantadine
• Anticholinergics Artane
Tolcapone and Entacapone

The catechol-O-methyl
(COMT) transferase inhibitors
are the most recent addition
to the antiparkinsonian
armamentarium. They
decrease removal of L-dopa
and thereby augment its
effects.
 Treament

• Amantadine may be helpful for the early

treatment of bradykinesia, rigidity, and gait
disturbance
• Anticholinergics Artane Because the drug
side effect is rarely used
Rehabilitation for Parkinson’s Disease
Surgical Therapy- Deep brain
stimulation
• Deep-brain-stimulation
surgery is appropriate for
select patients who are
generally physically healthy,
cognitively intact, and
emotionally stable, with a
strong family support system,
but who are bothered by
symptoms of parkinson
diseases (such as tremors),
motor fluctuations, or
dyskinesias
Managing of PD
Generic model of self-mangement
A care model for pwp
 Prognosis
• Before the introduction of levodopa, Parkinson disease
caused severe disability or death in 25% of patients within
5 years of onset, 65% within 10 years, and 89% within 15
years.
• The mortality rate from Parkinson disease was 3 times that
of the general population matched for age, sex, and racial
origin.
• With the introduction of levodopa, the mortality rate
dropped approximately 50%, and longevity was extended
by many years. This is thought to be due to the
symptomatic effects of levodopa, as no clear evidence
suggests that levodopa stems the progressive nature of the
disease
 summary
• PD is a neuros system degenaration disease
• The landmark sign of pathology is Lewy bodies
in neuros.
• Dapomine's depletion from the basal ganglia
is associated with the pathophysiology and
pathologic biochemistry of PD
• Symptoms including motor's and nonmoter's
• Managing patient can delay the progress of PD
and improve their life quality.
video
 Reference
• Frank W .Drislane et al Neurology(fourth
Edition).Wolters Klivwer.2014.