3. BG internal circuits
• There are three major divisions of
the striatum namely: sensorimotor,
associative, and limbic that are
related to motor, cognitive, and
emotional functions, respectively.
• Each circuit contains two pathways
by which striatal activity is translated
into pallidal output. These two
pathways are named the direct and
indirect pathways.
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4. General concepts ..
• BG output is mainly INHIBITORY.
• the only STIMULATING output from subthalamic
nucleus.
• Type of the circuit depends on OUTPUT from SNrGpi
• No direct connection with SC.
Input
Striatum
GPi/SNr
output
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5. BG connections ..
• + and - signs >> whether the
pathway is excitatory or inhibitory in
effect.
• Green arrows >> excitatory
glutamatergic pathways.
• Red arrows >> inhibitory
GABAergic pathways.
• Turquoise arrows >> dopaminergic
pathways.
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7. Direct Indirect
Important in
initiation and
maintenance of
movement
Plays a role in the
suppression of
extraneous
movement
The activity in the direct and indirect pathways mainly related to rates of firing in the STN and
GPi. Thus, death of neurons in the SNc, as in nigrostriatal degeneration associated with PD,
decreases activity in the direct pathway and increases activity in the indirect pathway.
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8. Shaking palsy
• The condition is named after James Parkinson who, in 1817,
described it in his work An Essay on the Shaking Palsy.
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9. Epidemiology ..
• Parkinson disease is a chronic, progressive, and disabling disorder
that is characterized by both motor and nonmotor symptoms.
• It is the second most prevalent neurodegenerative condition next to
Alzheimer disease.
• incidence estimates of Parkinson disease range from 5 to >35 new
cases per 100,000 individuals yearly.
• Parkinson disease is twice as common in men than in women in
most populations.
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10. Neuropathology ..
Characteristic features of Parkinson
disease include neuronal loss in specific
areas of the substantia nigra and
widespread intracellular protein
(α-synuclein) accumulation.
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11. Presymptomatic
stage
Pathology remains
confined to the
medulla oblongata
and olfactory bulb
Symptomatic stage
The substantia nigra
and other nuclear
grays of the
midbrain and basal
forebrain are
affected
The pathological
process encroaches
upon the
telencephalic cortex
Braak staging system11/3/2020 LA 2020
12. Etiology ..
• PD is a multifactorial illness with likely genetic and environmental determinants.
• Although the majority of cases of PD appear to be sporadic, it is becoming
increasingly evident that genetic factors play an important role in the
pathogenesis of PD, particularly if onset is earlier than age 50.
• It is estimated that 5% to 10% of patients have a genetic etiology for the disease.
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13. Genetic causes ..
• A growing number of novel
genes have been implicated in
the pathogenesis of PD.
• Currently, 20 specific
chromosomal loci are termed
PARK ( to denote their
association with PD), and
numbered in chronological
order of identification.
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14. Environmental causes ..
• Interest in whether environmental or toxic exposures can contribute to the development of
Parkinson disease was sparked by the association between 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP), a prodrug to the neurotoxin MPP+, and parkinsonism during the
1980s.
• Some of the environmental factors and toxic exposures that may be associated with Parkinson
disease include:
Pesticides (rotenone and paraquat).
Heavy metals (manganese, lead, and copper).
Well water.
Woodworking.
Head injury.
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15. Clinical symptoms ..
Motor
Four cardinal
• Tremor
• Rigidity
• Bradykinesia
• Postural instability
secondary motor
symptoms
• Diminished arm swing
• Decreased blink rate
• Masked facies (hypomimia), Decreased
voice volume
• (hypophonia)
• Difficulty turning over in bed.11/3/2020 LA 2020
16. • Often the first motor symptom of Parkinson disease.
• Typically a resting tremor.
• Start asymmetrically.
• Pill-rolling in character.
Tremors
• Stiffness or resistance of a limb when it is flexed passively.
• Cogwheeling.
Rigidity
• Slowness of movement, may occur during both initiation and continuation of
movement.
Bradykinesia
• Later in the course of the disease.
• Correlates with disease severity and is elicited by the pull test.
• A major cause of falls.
Postural instability
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20. Defined as symptoms that predate onset of
motor symptoms of PD
ANOSMIA
DEPRESSION
REM-SLEEP
BEHAVIOUR
DISORDERS
CONSTIPATION
Pre-motor
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24. Neuroradiology..
• CT and MRI are also usually unhelpful in making a diagnosis of PD, because they
are generally normal or show only incidental abnormalities.
• Can be useful in suggesting alternative diagnoses such as PSP or MSA.
• PET scans using this radiopharmaceutical agent show reduced F-dopa uptake in
dopaminergic nerve terminals in the putamen and caudate proportional to the
severity of degeneration in the ipsilateral SN and symptoms in the contralateral
hemi body.
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25. • In 2011, the US Food and Drug Administration approved dopamine transporter
SPECT using ioflupane I-123 injection.
• Dopamine transporter SPECT has a high sensitivity (87% to 98%) and specificity
(80% to 100%) when differentiating Parkinson disease from essential tremor.
• However, dopamine transporter SPECT is not a confirmatory test for Parkinson
disease, nor is it intended to differentiate between Parkinson disease and other
degenerative forms of parkinsonism, including atypical parkinsonism.
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27. Dopamine
agonist
Directly stimulate
dopamine receptors
Used as both
monotherapy and
adjunctive therapy in
treatment of PD
Longer half-lives
>6 hours
Higher incidence of
psychiatric side effects
(hallucination – impulse
control disorders) and
sleep attacks
Pramipexole, Ropinirole,
Rotigotine, Apomorphine
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28. COMT inhibitors
• Reduce the breakdown of levodopa to 3-O methyldopa
and increase the plasma half-life of levodopa.
• Used in conjunction with levodopa to improve end-of-
dose wearing-off time.
• Currently available COMT inhibitors include
ENTACAPONE AND TOLCAPONE.
• Carries a black box warning for potential liver toxicity.
• Increase dyskinesia.
MAO-B inhibitors
• Prevent levodopa degradation in the brain and limit its
reuptake.
• They were initially thought to provide antioxidative
properties in patients with PD.
• SELEGILINE, a selective and irreversible MAO-B
inhibitor approved as adjunctive medication to levodopa
in patients with motor fluctuations.
• RASAGILINE, a second-generation MAO-B inhibitor,
lacks the amphetamine metabolites of selegiline and may
be used as monotherapy and adjunct therapy.
• SAFINAMIDE is another potent, reversible MAO-B
inhibitor that has been recently approved as adjunct
therapy in PD patients with motor fluctuations.
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29. N-methyl-D-aspartate
(NMDA) receptor
antagonist
Amantadine
• Was originally used as an antiviral
medication in the 1960s.
• Has anti-dyskinetic properties.
• A newer preparation of amantadine,
ADS-5102, is an extended-release
form of amantadine that may be used
to treat levodopa-induced dyskinesia.
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32. Therapeutic approach..
When a patient is newly diagnosed with Parkinson disease, it is important to
determine whether symptoms are bothersome enough to the patient to warrant
treatment while also keeping nonmotor symptoms in mind.
Factors to be taken into consideration are the patient’s age, comorbid conditions,
employment status, and other quality-of-life issues
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33. Dopamine agonists, MAO-B inhibitors,
or anticholinergic medications may be
initiated in patients with Parkinson
disease who are younger than 70 years
of age.
Treatment with levodopa should be
considered if symptoms are bothersome
enough to cause suffering or interfere
with qualify of life.
Young
Patients with evidence of cognitive
decline, excessive daytime sleepiness,
or other comorbid conditions, it is more
appropriate to initiate treatment for
Parkinson disease with levodopa.
Dopamine agonists, MAO-B inhibitors,
and anticholinergic medications are
more likely than levodopa to cause
cognitive side effects in the elderly.
Old
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34. Minimize
troublesome
levodopa-
induced
dyskinesia
Reduce off-time
Taking Parkinson disease
medications more frequently.
Using an extended release
form of levodopa.
Adding a COMT inhibitor or
MAO-B inhibitor, or by the
addition of a dopamine agonist
to provide a more stable
response.
Redistribution of medication
doses.
changing forms of medication
from immediate-release to
extended-release formulations.
Amantadine has been shown to
treat levodopa-induced
dyskinesia.
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35. Surgical treatment..
• For patients who, despite medication optimization, experience motor
symptoms that cannot be satisfactorily ameliorated by medication.
• A common surgical treatment is DBS, which targets the
subthalamic nucleus, globus pallidus internus, or ventral
intermediate nucleus of the thalamus for tremor-predominant PD
with otherwise minimal symptoms.
• It has been demonstrated to improve tremor, dyskinesia, and motor
fluctuations.
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36. • Exclusionary criteria for DBS include: the presence of an
atypical parkinsonism, unstable psychiatric disease, advanced
disease with significant dementia, comorbidities that preclude
surgical candidacy, and advanced age.
• Possible complications of DBS include medical issues such as
myocardial infarction, pneumonia, deep vein thrombosis, and
pulmonary embolism and surgical issues such as cerebral
hematoma, stroke, seizures, infections, and hardware dysfunction,
all reported in a small percentage of patients.
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38. References ..
Direct and indirect pathways of basal ganglia: a critical
reappraisal – Nature.
Parkinson disease – Nature primer.
Parkinson disease and other movements disorders – Bradley’s
neurology in clinical practice.
The Role of Functional Dopamine-Transporter SPECT Imaging
in Parkinsonian Syndromes – AJNR.
Parkinson disease – continuum 2019.
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Editor's Notes
Neurologists often equate movement disorders with disease or dysfunction of the basal ganglia, so no review of movement disorders would be complete without a discussion of basal ganglia anatomy, physiology, and pathophysiology.
For the purposes of this discussion, we consider those structures in the striatopallidal circuits involved in modulation of the thalamocortical projection: the caudate nucleus, the putamen, the external segment of the GP (GPe), and the internal segment of the GP (GPi). In addition, the SNc, the substantia nigra pars reticulata (SNr), and the STN are included in the basal ganglia
http://www.neuroanatomy.wisc.edu/coursebook/motor2.pdf
Within each basal ganglia circuit lies an additional level of complexity.
Although neither the loss of pigmented dopaminergic neurons in the substantia nigra17,18 nor the deposition of α‑synuclein in neurons is specific for Parkinson disease, these two major neuropath ologies are specific for a definitive diagnosis of idiopathic Parkinson disease when applied together.
Photo>>Selective loss of the ventrolateral parts of the SN with sparing of the more medial and dorsal regions is evident in the histological
section. b–d | Haematoxylin and eosin staining of the ventrolateral region of the SN showing a normal distribution of pigmented neurons in a healthy control (part b) and diagnostically significant moderate (part c) or severe (part d) pigmented cell loss in PD
In the last 20 years, there has been increasing recognition of the importance of nonmotor symptoms
The impact from nonmotor symptoms is often greater than that of motor symptoms
Fig. 96.5 Positron emission tomography scan with [11C]RTI-32,
which labels the presynaptic dopamine transporter in a normal
control (A) and a subject with early Parkinson disease (PD)
(B). There is asymmetrically reduced uptake in PD, indicating asymmetrical
loss of presynaptic dopaminergic neurons.
Normal study findings. The axial 123I-FP-CIT DaT-SPECT image
demonstrates symmetric tracer uptake in the caudate nuclei and putamina, with very low-grade, almost absent, background activity
. Axial 123I-FP-CIT DaT-SPECT sections depicting the different patterns of abnormality seen in PD as described by Catafau and Tolosa2
—
type 1: asymmetric activity with reduced putaminal uptake in 1 hemisphere (A); type 2: symmetric reduction in putaminal uptake in both
hemispheres (B); and type 3: virtual absence of uptake in the putamina and caudate nuclei despite high gain as demonstrated by ample
background activity (C)
http://www.ajnr.org/content/ajnr/36/2/229.full.pdf
Several studies suggest that starting treatment with levodopa leads to better long-term motor outcomes and better functioning long-term.
Motor fluctuations and dyskinesias may be more closely associated with longer disease duration and higher levodopa daily dose rather than the duration of levodopa therapy.67 Pulsatile delivery of levodopa also contributes to dyskinesia
