Pathophysiology of Parkinson's disease

The
neurons of the corpus striatum receive excitatory input from the cerebral cortex
and on thalamus. thalamus. The major outputs project to the entropeduncular/ ent
ropeduncular/ substantia nigra (EP/ SNr) nuclear complex and the SNr) globus pal
lidus Neurons from the EP/ SNr complex project to the ventral tier and intralamin
ar thalamic nuclei and to the superior colliculus and the pedunculopontine nucle
us. nucleus.
to the striatum occurs through the dopaminergic nigrostriatal pathway  The inhibi
tory output of nigral neurons is phasically inhibited in turn by cortical activi
ty expressed through the striatonigral pathway. pathway.  Striatal outputs use ga
mma-aminobutyric acid gamma(GABA) as a transmitter  direct striatonigral pathway
together with an indirect pathway via the globus pallidus and the subthalamic nu
cleus. nucleus.
 Feedback
 The
direct pathway is inhibitory, and the indirect pathway modifies the excitatory i
nput from the subthalamic nucleus to the substantia nigra  Depletion of dopamine
in the striatum results in increased activity of the striatopallidal pathway and
decreased activity in the striatonigral pathway. pathway.These effects lead to
increased activity of the GABAergic neurons of the output nuclei of the basal ga
nglia. ganglia.  Increased inhibitory output from these nuclei may be responsible
for the bradykinesia seen in patients with Parkinson's disease
Figure 1 :Major pathways of the basal ganglia
Thalamus
Basal ganglia GL GL CN GL GL ACh
Ventral lateral nucleus, ventral anterior nucleus (thalamus)
Putamen MSN
GABA,Enk DA
GL GABA
GABA
GPi STN GPe
GABA,SP GL GABA
Direct pathway Neurotransmitters: GL: Glutamate ACh: Acetylcholine DA: Dopamine
SNr SNc
Connections: Red: Excitatory Blue: Inhibitory Green: Excitatory and Functional o
rganization (left, normal; right, Parkinson disease) inhibitory
Parkinson¶s disease
Any discussion of the clinical characteristics of Parkinson's disease must take
into account the inaccuracies of clinical diagnosis. In a successive series of 1
00 patients with a clinical diagnosis of Parkinson's disease, only 76 fulfilled
the criteria for diagnosis at postpostmortem examination (Table 1).
Table 1: Pathological findings in 100 successive Parkinsonian patients
Idiopathic Parkinson's disease Progressive supranuclear palsy Multiple system Al
zheimer's disease Alzheimer-type pathology with striatal involvement Lacunar sta
te Nigral atrophy Postencephalitic Parkinsonism Normal (essential tremor)
76 6 5 3 3 3 2 1 1
Epidemiology
The prevalence of Parkinson's disease has been reported to lie between 30 and 30
0 / 100 000, 000, producing approximately 60 to 80 000 cases in the United Kingd
om
Clinical features
Typically, the condition produces:  Bradykinesia  Tremor  rigidity  impairment of po
stural reflexes.  An asymmetrical onset is characteristic.
Bradykinesia

initially, leading to difficulty with fine tasks, such as manipulating a knife o
r fork, dressing or shaving .The patient¶s handwriting typically becomes reduced in
size if the dominant hand is affected .
Figure 3 : Micrographia in Parkinson's disease: The script is progressively redu
ced in size
reduction of arm swing when walking. Facial immobility is evident, with a lack of
animation and immediate emotional response .
Figure 4: Characteristic facial appearance in Parkinson's disease
Walking becomes slowed, with a tendency to reduce stride length and an increased
number of steps being taken when turning .
Figure 5: Posture of a patient with early Parkinson's disease
Figure 6: Late stage of parkjnson`s disease
Rigidity
It persists throughout the range of motion of any affected joint. A characterist
ic judder (cogwheeling) occurs at (cogwheeling) a frequency similar to that of t
he postural tremor seen in Parkinson's disease rather than at the rate of the re
sting tremor. If the rigidity is equivocal, it can be activated by contracting t
he contralateral limb.
Tremor

The classical Parkinsonian tremor occurs at rest, at a frequency of around 3±4 Hz .
Figure 7 : Power-spectrum Power(upper) and accelerometer (lower) tracings taken
from a patient with Parkinsonian tremor. The main tremor tremor. peak is at appr
oximately 5Hz with a harmonic at 10 Hz
Figure 8 As this patient repetitively clenches and unclenches his fists, a pauci
ty of movement is apparent in his left hand
Postural reflexes
In addition to abnormalities of posture, the patient has difficulty maintaining
posture when suddenly pushed forwards or backwards autonomic dysfunction (princi
pally in the form of urinary urgency and occasional incontinence)
Figure 9 Positive glabellar tap. Persistent blinking is a feature of Parkinson¶s di
sease, but is also seen in Alzheimer¶s disease
Drug intervention
Figure :10 :10 Synthesis and metabolism of dopamine within the CNS
Parkinsonian syndromes
A vast number of disorders can produce a clinical picture which closely resemble
s Parkinson's disease (Table 2).
Table 2: Disorders with clinical presentations similar Parkinson¶sSymptomatic Parki
nsonism disease
Postencephalitic Drug-induced Toxic Traumatic Arteriosclerotic Normal-pressure h
ydrocephalus Striatonigral degeneration Parkinsonism in other degenerative disor
ders Progressive supranuclear palsy Corticobasal degeneration Diffuse Lewy body
disease
Postencephalitic Parkinsonism
Clinical features include oculogyric crises, behavioral disorders, pyramidal tra
ct signs and various movement abnormalities.
DrugDrug-induced Parkinsonism
Any drug affecting the synthesis, storage or release of dopamine, or interfering
with dopamine receptor sites, is capable of causing an akinetic rigid syndrome
which may closely resemble idiopathic Parkinson's disease. The condition tends t
o be symmetrical and to lack tremor .
Arteriosclerotic Parkinsonism
Certain clinical features were held to distinguish arteriosclerotic Parkinsonism
from idiopathic Parkinson's disease, including the lack of tremor, a predominan
ce of gait involvement over upper limb disorder
Cortical Lewy body disease
In patients with Lewy body dementia, the dementia may precede, coincide with or
follow the extrapyramidal features. Early onset of paranoid ideation accompanied
by visual hallucinations.
Progressive supranuclear palsy (Steele±Richardson± (Steele±Richardson±Olszewski syndrom
A disturbance of gait is common and many patients are liable to falls. The body
tends to remain falls. extended rather than taking on the stooped posture of Par
kinson's disease .
Striatonigral degeneration
Striatonigral degeneration has considerable clinical overlap with Parkinson's di
sease, but sufficient differences to suggest the diagnosis in life. Rest tremor
in the early stages of the disease is distinctly uncommon
Figure 11: In this patient with progressive supranuclear palsy, 11:
upward (A) and lateral gaze (B and C) are preserved whereas down gaze (D) is imp
aired
A
B
C
D
Multiple system atrophy
Both bradykinesia and rigidity are likely, but a classical resting tremor is unu
sual.
MRI identifies sites of maximum atrophy in the brain stem and cerebellum. The mi
ddle cerebellar peduncle shows the most marked reduction in size
Corticobasal degeneration
This disorder bears some superficial resemblance to PSP, but has distinctive cli
nical and pathological features which distinguish it.  The gross pathological fin
dings include a marked asymmetrical frontoparietal atrophy with relative sparing
of the temporal cortex

Figure 12 : In this patient with corticobasal degeneration, sagittal T1-weighted
MRI (left) shows predominantly posterior frontal an parietal atrophy (arrowed).
Coronal T2-weighted MRI (right) T2 shows that the parietal atrophy is asymmetri
cal
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